2012 Best Practices for Repositories Collection,Storage,Retrieval,and Distribution of Biological Materials for Research International Society for Biological and Environmental Repositories

A2.100 Models

The collection and storage of specimens may be performed in support of a variety of scientific endeavors. Specimens may be collected as a part of prospective or retrospective studies and the method of procuring these specimens will depend on the availability of resources and the particular scientific inquiry. There are several models for how specimens may be procured, stored and prepared for subsequent testing. A repository may take advantage of a single approach or multiple approaches to achieve its scientific mission. Once a repository is established in support of one model, it should be easier to expand the infrastructure to include other models as needed rather than to initiate a new repository from the beginning. This approach prevents duplication of efforts and allows more efficient utilization of resources. Regardless of the model employed, specimens should always be collected and processed according to the most current methods supported by scientific data and best practices, where possible.

A2.200 Organizational Considerations

When planning a repository, it is important that the mission of the repository be clearly defined. The mission should address the purpose of the repository and the entities served by the collections obtained. The mission should be reviewed over time to ensure its appropriateness as conditions surrounding its implementation may change. It is important that the equipment, facilities, staffing and funding for a repository be established according to a structure that will support the mission and activities during the anticipated lifecycle of the repository. Policies must be created, enforced and reviewed on a regular basis concerning specimen access, handling, culling and for the termination of the repository.

A4.100 Director

The Director is the person with overall responsibility for management of the repository. The Director should be qualified by training and experience to direct and manage the scope of activities conducted by the repository.

A4.200 Technical Staff

Staff should possess sufficient educational background, experience and training to assure that assigned tasks are performed in accordance with the repository's established SOPs. Technical staff should be responsible for adherence to policies and SOPs as established by the Director. Duties of each staff member should coincide with written job descriptions. Staff should demonstrate competency in operations for which they have received training and to which they are assigned. Authority and reporting relationships for each member of the staff should be clearly described.

A5.100 Outsourcing Services

Careful planning during the development phase is critical to repository quality and cost-efficiency. Where internal resources are not sufficient to provide all necessary expertise, either during development or as a repository evolves, a repository may seek assistance from qualified external experts and consultants. Consultants should have documented successful experience (similar to that which would be sought for internal staff) in the area for which they are retained. Repository consultants may provide expertise in areas such as strategic planning, equipment selection and decisions surrounding automation, SOP development, vendor selection, grants and cost recovery, contract management, quality assurance and regulatory affairs. Similarly, the repository may have contractual relationships with other institutions or service providers that provide access to facilities or services not available at the parent institution. In all of these situations, the Director should have clear documentation of the relationships, expectations, and responsibilities.

B2.100 Temperature and Humidity

In most repositories it is critical to maintain ambient temperature within defined limits. Sufficient heating capacity should be provided to prevent the freezing of water in drain lines. Likewise, sufficient air conditioning should be provided to prevent excess load on the compressor systems of mechanical freezers and refrigerators that may result in excess wear and early failure. Humidity level restrictions may need to be considered when storing at ambient conditions.

Best Practice: For optimal life of the mechanical refrigeration equipment, repository ambient temperatures should be monitored and not allowed to exceed 22 °C (72 °F). This is particularly critical for rooms containing multiple mechanical units.

B2.200 Air Flow and Circulation

Sufficient air circulation should be provided to prevent excess moisture and condensation. Excess humidity can lead to fungal growth if left unchecked, which may affect specimen integrity and cause health problems for staff. Sufficient space for air circulation is required especially in areas where freezers and refrigerators are employed to prevent excess heat accumulation which may negatively affect compressor function (see Section C3.000, Mechanical Freezers). Adequate ventilation and monitoring are also critical in repositories where liquid nitrogen and dry ice are used to ensure that sufficient oxygen levels are maintained (see Section C2.400, Oxygen Sensors). Similarly, when services are performed in which potentially harmful vapors are generated (e.g., formaldehyde) the ventilation system should ensure that personnel are protected and that regional and national standards for the removal of specific harmful vapors are met.

Best Practice: It is recommended that appropriate monitoring devices (e.g., oxygen and CO₂ monitors) and exhaust systems are installed within areas where there is the potential for a low oxygen level to develop or harmful vapors to accumulate.

B3.100 General Lighting

Lighting in a repository should be sufficient to provide a safe working environment and to allow materials to be accurately put away and retrieved. The lighting levels required will depend on the particular spatial environment where the samples are stored, the type of activity that is being performed, the volume and specimen type, and the labeling/identification system employed.

Lighting may be both general and task, depending on the situation. General area lighting may be incandescent, fluorescent, metal halide, or other appropriate source. Some repositories may contain materials or specimens which are sensitive to light levels or to particular frequencies of light.

Best Practice: Appropriate lighting should be planned for and used during the storage and handling of materials or specimens determined to have sensitivities to certain lighting conditions.

B3.200 Task Lighting

Task lighting may be necessary to have sufficient illumination for tightly packed materials, reading labels, or where overhead lighting is impaired. In situations where task lighting is employed, care should be taken that the lighting method does not adversely affect the sample integrity and the storage conditions. For example, the heat from incandescent lighting placed too close to stored material may cause a sample to thaw or partially thaw.

Best Practice: Fluorescent lighting or another type of lighting that does not create a source of heat is recommended for use in task lighting near frozen materials.

B3.300 Emergency Lighting

In case of power loss it is critical that emergency lighting be available to indicate exit routes from the repository and to provide an illuminated, safe environment to aid in monitoring equipment and responding to the needs of the emergency. Emergency lighting should have battery backup support and should be tied to backup generators. It may be beneficial to use small night lights that plug into outlets that have a battery component for low level illumination. Repositories should also have portable lighting (e.g., flashlights) on hand to use as focused light sources, as needed. Focused light sources can be essential during an emergency for use in equipment diagnosis and repair. Emergency lighting should be tested on a regular basis and batteries checked on an annual basis and replaced as needed as a part of the overall safety and maintenance SOPs.

B5.100 Uninterruptible Power Supply

An uninterruptible power supply (UPS), uninterruptible power source or sometimes called a “battery backup” maintains a continuous supply of electric power to connected equipment when utility power is not available.

A UPS is inserted between the source of power (typically commercial utility power) and the load it is protecting. When a power failure or abnormality occurs, the UPS will effectively switch from utility power to its own power source almost instantaneously.

Best Practice: Computer systems and electronic systems, such as environmental monitoring systems, safety systems (e.g., oxygen sensors, ventilations systems) or controllers for liquid nitrogen freezers, should be protected by a UPS. UPSs used in repositories should be tested on an annual basis to ensure their proper backup capabilities.

B5.200 Generators

The most common type of backup power is a motor generator. Generators have automatic controls that cause them to produce electricity when commercial power is interrupted. Typically they are fueled by diesel, natural gas or propane. Where it is available and appropriate, natural gas supplied by a pipeline may serve as an optimal source, since it can serve as an unlimited source of fuel provided supply lines are not interrupted. The actual backup system employed should be determined based upon a risk management assessment of the facility, region and resources.

Dual fuel generators that can run on more than one type of fuel (e.g., natural gas and propane) provide a high level of flexibility for fuel supply sources. Manual transfer switches in addition to the automatic transfer switches can be installed which allow for set up of quick disconnects which enable portable generators to be brought in and connected in a matter of minutes. Each outage scenario and desired outcome needs to be evaluated up front to ensure expected infrastructure is in place. For large repositories, the decision to have one large generator or multiple smaller ones to support the facility will also come out of risk assessment exercises.

Based on risk tolerance assessments and financial stewardship, it may be determined that a backup generator support only designated pieces of equipment deemed critical.

Best Practice: A generator should have a fuel supply to run continuously for a minimum of 48 hours and preferably a minimum of 72 hours, with an ability to re-fill fuel storage supplies.

Best Practice: Repositories that utilize generators should have an established plan for sources to replenish fuel supplies in case of an emergency. This plan should include lists of suppliers and backup suppliers committed to provide the fuel as needed.

Best Practice: Repositories should contact suppliers to be placed on a list as an entity that receives a quick response should an emergency situation arise.

B6.100 Visitor Access Policy

An access policy should be developed for individuals visiting the repository. Where feasible and appropriate, sign-in sheets or log books should be used to record the name, affiliation of the visitor, purpose of the visit, as well as track the time at which the visitor(s) enters and leaves the repository. Badges can be made available for the visitors that clearly indicate to staff that they have been formally received and their presence documented. Visitors should be accompanied by staff at all times during their visit.

Best Practice: When written or electronic records of repository visitors are maintained, the records should be maintained and archived according to the repository's established archive practices.

B7.100 Intrusion Detection Systems

When either the repository or the building in which it resides is not occupied by authorized personnel, a system should be in place to detect unauthorized entry. Motion detectors, glass break and door entry sensors should be integral components of the system. As appropriate, the system should accommodate changes to security codes and keys when individuals leave the organization.

B8.100 Fire Prevention Plan

Repositories should have a written fire prevention plan. The plan should include a list of major fire hazards, potential ignition sources, proper handling and storage procedures for hazardous materials, and the type of equipment necessary to control each major hazard. The plan should address procedures for regular maintenance on equipment used to prevent or control sources of ignition or fires and name or job title of employees responsible for maintaining the equipment.

B8.200 Detection Systems

Automatic fire detection systems are used to quickly identify a developing fire and alert occupants and emergency response personnel before extensive damage occurs. Automatic fire detection systems do this by using electronic sensors to detect the smoke, heat, or flames from a fire and provide an early warning. Fire detection systems should be tested regularly to maintain proper reliability and operating condition by a trained person knowledgeable in the operations and functions of the system. Fire detectors should be selected based on the burning characteristics of the materials present and the nature of location they will be used to protect.

B8.300 Fire Extinguishing/Suppression Systems

B9.100 Emergency Response Planning

Emergencies can cover a wide range of natural and man-made disasters, all of which may have varying effects on the facility and on the ability of the repository to carry out its essential functions. The type and duration of disasters may depend on the geographic location at which the repository is located. Depending on the “value” and the ability to replace certain samples, some repositories may decide to divide collections and store them in different environmental storage containers or even at different geographic locations so that a disaster affecting one component of the collection would not eliminate the entire collection.

Repositories should have a written disaster recovery/incident response and business continuity plan for responding to a wide variety of emergency situations. This plan should be tested periodically (i.e., at least annually) to ensure that all personnel are trained and that the plan meets the anticipated needs. Copies of these plans should be distributed to all appropriate staff.

Key individuals should be identified who will serve as being “on call” or who will be able to respond to an emergency at the repository. Leave and vacation schedules should be monitored to ensure that coverage of essential responsibilities is in place should key individuals be unavailable. Emergency contact numbers should be posted in prominent locations in the repository and should be carried by staff members at all times who are “on call.” The contact information should be reviewed on a regular basis to ensure that the information contained therein is current.

Best Practice: The Director or appropriate staff member should communicate with local power providers before an emergency occurs to request that the repository be placed on a list of “high priority” users for power restoration following an emergency.

Best Practice: Repositories should have a check list of activities for “on call” staff to follow during an emergency. “On call” staff should be familiar with the location and operation of certain key equipment and controls (i.e., circuit boards) that may need to be checked during an emergency. Telephone numbers for professional assistance should be clearly posted in the repository and accompanying administrative areas (e.g., engineering or facilities personnel, power companies, fuel supply companies and transportation services).

Best Practice: Notification of security and environmental monitoring systems should be verified on a routine basis. Where possible, emergencies should be simulated to ensure proper follow-through for the established emergency plan.

Best Practice: If repository inventory systems are housed on a server located away from the repository, some consideration should be given to storing electronic inventory records on site. Otherwise, in an emergency, needed records may not be accessible.

Best Practice: In the event of an impending need for evacuation, repositories that utilize LN₂ bulk tank(s) should arrange to have them filled.

C2.100 Vapor or Liquid Storage

When considering storing in LN₂ vapor phase (≤−150 °C) vs. submersion in liquid phase (−196 °C), vapor phase storage is preferred because it provides sufficiently low temperatures to maintain samples below the Tg (Glass Transition Temperature; −132 °C) while avoiding the safety hazards inherent in liquid phase storage. Many commercially available vials are penetrable by liquid nitrogen so vials selected for storage should be tested before they are used. Certain containers, like cryogenic straws, are hermetically sealed and specifically designed for the safe storage of specimens in the liquid phase of nitrogen.

C2.200 Storage Containers

LN₂ expands 700 to 800 times its original volume when brought to a gaseous phase at room temperature. This situation may produce an explosion hazard. Glass, metal and some plastic containers can explode if LN₂ is trapped inside the container when it is removed from the freezer.

Best Practice: Any container used or stored at cryogenic temperatures should be rated for these temperatures.

C2.300 Liquid Nitrogen Supply

Where LN₂ refrigeration is employed, an adequate supply of LN₂ should be maintained. For freezers filled from Dewars or supply tanks, a minimum three-day supply of LN₂ at normal usage and replenishment intervals should be maintained, with the assumption that a re-supply is readily available. Bulk supply systems should maintain at least three days' working capacity. Bulk supplies should be checked for re-supply at least once a week. A telemetry system may be installed to allow suppliers to monitor liquid levels in real time to ensure stocks do not drop below agreed upon levels.

Bulk storage and piping systems require relief valves to prevent rupturing of the pipe and bulk tanks in the event of over-pressure. If relief valves trip unexpectedly, a person near a valve can be sprayed with either the cold gas or the liquid. More likely, in the event of a blockage or excessive pressure, a number of relief valves may vent nearly simultaneously. This can cause a “whiteout” condition in a matter of a few seconds. Visibility can drop to near zero and oxygen levels in the area may become less than that necessary to sustain life. Under these circumstances personnel should evacuate immediately. For this reason, O₂ monitoring should be installed in any areas of the facility where bulk LN₂ is utilized (See Section C2.400, Oxygen Sensors).

Best Practice: Daily LN₂ usage should be recorded either by monitoring the display levels or by manual means as excessive LN₂ usage can indicate problems with the vacuum component of the freezer.

C2.400 Oxygen Sensors

Because nitrogen displaces oxygen, care should be taken when LN₂ freezers are employed. The risk is inversely correlated with the size of the room. Oxygen level sensors should always be employed when LN₂ freezers are used in a repository. Normal levels of oxygen in ambient air should be ∼21%. Most installed oxygen sensor units have batteries or sensor cells that should be replaced and re-calibrated every few years. Consult the manufacturer for recommended requirements.

Both fixed and mobile/personal monitors may be appropriate depending on the size of the facility. Even when installed units indicate an alarm condition, it may be useful to employ a personal monitor to enter the room carefully to validate the alarm condition if the area is not visible from the outside. Mobile oxygen monitors may be the best to use in a secure area where LN₂ freezers operate because the sensors in installed units will degrade over time and sound false alarms.

C2.500 Personal Protective Equipment

In addition to the oxygen deficit risks described under Section C2.400, use of LN₂ as a refrigerant poses special safety problems because of its low temperature and rate of expansion when placed at ambient conditions. Eye protection is mandatory every time LN₂ is handled to protect against splashes that inevitably occur. Face and eye protection is recommended when handling vials removed from a LN₂ freezer or when dispensing LN₂ from low pressure lines. Heavy gloves (appropriate for LN₂ use) should be worn to protect hands when handling samples stored within the liquid phase or when transferring LN₂ or other coolants to Dewar flasks. Normal laboratory personal protective equipment (e.g., closed toed shoes, full cover of legs and feet and goggles) should be worn when handling coolants. The use of protective equipment, goggles and gloves, in particular, should be mandatory when handling cryogenics and the equipment should be placed in an easily accessible and visible location. Appropriate training in the safe handling of cryogenics should be provided and included in an SOP, describing the potential health hazards and required safety precautions.

C5.100 Compressors

For the storage of valuable materials, walk-in refrigerators and freezers should be equipped with dual compressors that operate under an electrical alternating control system.

C5.200 Door Release

In most countries building codes require that walk-in units have internal safety releases to prevent a person from being trapped within a unit by the accidental closing of doors (e.g., interior door release mechanism).

C5.300 Floor Covering

Refrigerators can generate slipping and falling hazards if water condenses on the floor. Freezers can occasionally create ice on the floor, or water if the unit is defrosting. Some type of mat or grate should be placed in front of these types of units to prevent slipping.

Best Practice: A warning sign should be posted at the entrance of walk-in cold storage areas advising that the area may be slippery.

C5.400 Dry Ice

Walk-in freezers should be kept free of dry ice (i.e., the solid phase of CO₂). Carbon dioxide can rapidly build-up, displace the oxygen in the room, and cause personnel working in the units to lose consciousness. In confined areas the CO₂ can displace oxygen, presenting an asphyxiation hazard. Where dry ice is employed there should be adequate ventilation to ensure that sufficient air or oxygen levels exist. In these circumstances, it is recommended that walk-in freezers have both oxygen and CO₂ monitors.

C5.500 Motion Detection Devices

Because of the special hazards involved in personnel working in a −20 °C or colder walk-in environment, it is desirable that some form of monitoring system be employed. This is especially applicable if only one person is working in the freezers. Systems which detect and alarm when motion does not occur are readily available (such systems are commonly employed by firefighters and other emergency personnel.)

Best Practice: For a −20 °C or colder walk-in environment engineering controls may be designed to support an audible alarm system coupled with a safety procedure to allow for the safest operating conditions.

C5.600 Contamination Issues

Contamination by fungus can frequently develop in cold rooms. This is facilitated by storage of non-specimen materials in containers such as cardboard boxes. It is, therefore, important to periodically survey the cold area to eliminate factors (e.g., damp, unclean areas, cardboard boxes) that can facilitate fungal growth. Similarly it is not appropriate to use cold rooms to store hazardous or flammable material, or food. Periodic monitoring of cold rooms should be encouraged to visually monitor for fungal contamination and for items that may be inappropriately stored. Repositories should consider the use of built-in dehumidification systems.

C9.100 Calibration

A system for the calibration of all instruments should be in place. Any device that provides analog or digital measurements is considered an instrument and requires calibration. Calibration should be done annually or per manufacturer's recommendation. Calibration should be performed against standards established for the country in which the repository resides.

Best Practice: Calibration records should include the appropriate standard readings taken both before and after calibration.

Best Practice: A log of calibration records should be kept that includes the date of the calibration, the name of the individual performing the calibration, the name of the device used against which the instrument is calibrated, and a reference to the standard operating procedure used to perform the calibration.

C9.200 Verification of Equipment Functionality

The proper performance of all equipment should be verified or qualified prior to use or following repairs that affect the instrument's measuring capabilities. Documentation of the testing should be maintained and made available for audits. The repository Director should ensure that all required regulatory practices are implemented.

C9.300 Equipment Preventative Maintenance and Repair

Essentially all equipment comprised of multiple components wears out with time and exposure to various environmental conditions. The duration of the lifetime for equipment used in the repository may be significantly extended by performing routine assessments and modifications to the equipment according to the manufacturer's specifications. For mechanical freezers this may include a periodic changing out of fluids, cleaning of filters, calibration of probes, or manually removing ice from the tops and sides of the interior chamber of the freezer. Routine maintenance recommendations should be determined before a piece of equipment is put into service. Frost-free freezers should be avoided, since the daily heating cycle built into the doors of these models will gradually cause deterioration/desiccation of specimens stored near the doors and walls of the unit.

Maintenance records should provide a description of the cause of the equipment failure (where possible), the date on which the incident occurred and was observed (these dates may be different), the corrective action that was taken, tests that were performed to verify proper functioning of the equipment, and the results compared to available standards and manufacturer recommendations.

Best Practice: Well-qualified personnel with expertise in monitoring and repairing repository equipment (especially freezers and refrigerators) should be used for regular and emergency repairs. These trained technicians may be on the repository staff, may be on staff within the larger organization within the institution in which the repository resides, may be available through a “fee for service” arrangement with a commercial entity with this expertise, or repair services may be obtained from a similar entity on a retainer basis.

Best Practice: Repositories should maintain spare parts for critical equipment, especially for aging equipment for which parts may not be readily available.

C9.400 Repair vs. Replacement

While most manufacturers of repository equipment offer projections for the expected lifetime of that equipment, actual lifetimes vary depending on a variety of factors including preventative maintenance, availability of replacement parts, environmental conditions in the area in which the equipment is located, etc. For example, manufacturers of mechanical freezers offer projections of lifetimes that range from 8–12 years, but actual lifetimes might run for a period of 5 to 15+ years. Liquid nitrogen freezers may have lifetimes extending through 10 to 35 years.

Long-range plans should be made to address the possible repair and replacement of equipment essential to the functioning of the repository. When multiple repairs are required, the additional cost of making those repairs may lead to a decision to have the unit replaced. Since replacement of freezers and refrigerators can be expensive, it is best to anticipate these costs and have some financial reserves available to address this when decisions to replace equipment are made.

Best Practice: Repositories should plan for the orderly replacement of equipment. If multiple pieces of the same equipment need replacement at one time, it might be best to use interim equipment or backup equipment while introducing the new equipment in over time. This allows for a gradual introduction of new equipment so that likely repair and replacement schedules are likely to be staggered.

Best Practice: Resources for equipment repair and replacement should be identified when the repository is being established before an emergency is experienced. These resources should be reviewed on an annual basis.

Best Practice: Before new equipment is purchased, an evaluation should be performed to identify the most energy-efficient equipment that effectively addresses the needs for that equipment. Attention should be given to the expected life of the equipment (e.g., mean time between failures).

D3.100 Essential Components for Standard Operating Procedures

SOPs serve as the description of how tasks pertaining to repository operations should be handled by staff assigned to those specific responsibilities. SOPs allow for uniformity and reproducibility in specimen handling. SOPs should be written by an individual or group of individuals with experience in successfully performing the processes described and should be managed in a document management system (see Section G, Records Management). Draft SOPs should be reviewed before they are finalized.

Essential features of an SOP are included in the following list of components:

• Title – a unique name which captures the essence of the practice described.

D3.200 Critical Topics for Manual of Operations

The manual should specifically include, but should not be limited to procedures regarding the following:

• Specimen handling.

D3.300 Implementation

Either the repository Director and/or the individual responsible for the QA Program should review and approve all SOPs and associated process validation studies prior to implementation. Upon implementation, all SOPs should be followed as written.

D3.400 Modifications

D3.500 Review of Standard Operating Procedures

SOPs should be reviewed regularly (at least every two years or when policy or methods change) to ensure the current policy and/or method for performing the procedure is described. A system should be in place to document the revision number and date of release of the revised document.

D3.600 Staff Access and Review

Current copies of the SOPs should be stored in designated locations and available to the staff at all times. New and revised policies and procedures should be read by the staff prior to implementation.

Best Practice: A system should be in place to document staff review of the most recent versions of an SOP.

Best Practice: Training associated with SOPs should be maintained in a training record (see Section F2.700, Training Records).

D4.100 Current Good Practices

Current Good Practices (cGP) are regulatory guidelines that should be interpreted by the repository to fit its particular circumstances. cGP may be preclinical (Good Laboratory Practice, or GLP), clinical (Good Clinical Practice or GCP) or manufacture (Good Manufacture Practice, or GMP). cGP may be more relevant to large corporate repositories, but academic and other small repositories may wish to aim toward cGP guidelines to instill confidence in the implementation of their SOPs. Generally, these standards are interpreted as follows:

• The facility is in a secure, locked area with limited access for unauthorized persons.

D4.200 Best Practices

Best Practices reflect a consensus body of recommendations made by individuals working in and with repositories. These Practices are not binding but rather reflect the knowledge and experience of this community. Best Practices go above and beyond standard recommendations and may be cost-prohibitive in some cases. Repository management and other staff should decide which practices to adopt that best support their particular circumstances.

D4.300 International Organization for Standardization

ISO9001 was created through the International Organization for Standardization (ISO). ISO is a worldwide federation of national standards with headquarters in Geneva, Switzerland. The organization was founded in 1946 to develop a common set of standards for manufacturing, trade and communications organizations.

• ISO9001:2000 Requirements of Quality Management Systems - a system standard, not a product standard. Its primary purpose is to provide organizations with useful internationally recognized models for operating a quality management system. Specifies requirements for a quality management system where an organization needs to demonstrate its ability to consistently provide products that meet customers' and applicable regulatory requirements.

D4.400 Clinical and Laboratory Standards Institute (CLSI)

Different standards have been published by the CLSI which, although developed for clinical laboratories, may also be relevant to biorepositories. Relevant CLSI standards include the following:

• CLSI H3-A6 Procedures for the collection of diagnostic blood specimens by venipuncture; approved standard-sixth edition.

D6.100 Pre-analytical Variations

Features of biospecimen quality; including structure of proteins, function of enzymes, level of metabolites, gene expression levels, DNA methylation status, cell viability, microorganism viability can be affected by the specific procedures followed during sample collection, transport, processing and storage. In vivo pre-analytical variations include the patient's clinical condition, timing of collection (e.g., pre-operative, post-operative), medication, diet, stress, circadian rhythms or the non-human specimen's environmental niche/ type of habitat, host, axenic state, season of collection and microbial phase variation which are difficult to control and standardize and should be considered as part of the inter-individual variation of the collection. These variations should be noted whenever possible and appropriate. In vitro pre-analytical variations include the type of collection tube, pre-centrifugation delay and temperature, centrifugation details for biological fluids, warm and cold ischemia times for solid tissues, type of sampling, type and time of fixation, time delay before placing into long-term storage, type of long-term storage and exact protocol of cryopreservation and of restoration for environmental specimens. These elements should be tracked in an appropriate manner (e.g., SPREC, Betsou and the ISBER Working Group on Biospecimen Science, 2010).

D7.100 Quality Control Consideration for Human and Animal Biospecimens

D7.200 Quality Control Considerations for Microorganisms

Phenotypic characterization includes both macroscopic and microscopic morphology assessment. Genotyping (e.g., DNA sequencing, PCR-based profiling, microarrays), ribotyping, classical biochemical tests and/or serotyping methods can be applied for taxonomical identification purposes. Functional assays include viability assays, or assays for cytopathic effects.

Quality Control for purity can be performed; however, certain cultures need to be maintained in a non-axenic state (e.g., obligate plant pathogens and assemblages of microorganisms, symbiotic and beneficial associates found in microalgae and cyanobacterial collections).

D7.300 Quality Control Considerations for Plant Specimens

The overarching QC process of plant biorepositories (i.e., gene banks, culture collections, germplasm repositories, seed and field banks) ideally involves germplasm characterization before and after storage and at the point of dissemination as well as plant health (phytosanitary) checks, safety duplication and passport documentation with assignment of an accession number.

In the case of seed materials, the International Seed Testing Organization (ISTA) has the mission to develop and publish standard procedures in the field of seed testing and encourage and establish uniformity in seed testing world-wide.

For clonally propagated plants (and other non-seed genetic resources such as pollen and dormant buds) quality testing includes assessment of viability, phytosanitary status and disease management (e.g., comprising quarantine, disease indexing and eradication).

Phenotype and genotype authentication can be a regulatory requirement for some crops and commercial forestry species and can include formal confirmation of certification status (trueness-to-type) by field-testing plants that are evaluated using specific phenotypic descriptors and as appropriate confirmation using molecular markers.

The detection, expression and stability of genetically modified materials may be necessary. The risk assessment and management of transgene contamination is a requirement for certain types of collections.

Post-storage QC measures include assessments of viability, morphogenetic competence, totipotency, regeneration, biochemical stability (e.g., for secondary product producing cell lines) phenotypic and genotypic stability (e.g., characterization of somaclonal variation) and trueness-to-type assessment under field or glasshouse conditions using descriptors.

D7.400 Quality Control Considerations for Nucleic Acid Specimens

DNA and RNA can be assessed for integrity and fragmentation (e.g., molecular weight; RNA Integrity Number), quantity/concentration and purity. DNA can be assessed for the absence of cross-linking, the absence of PCR inhibitors, the bisulfate conversion rate and the methylation status. RNA can be assessed for amenability to reverse transcription and the maximum length of the quantitative real time polymerase chain reaction (qRT-PCR) products.

D7.500 Validation of Quality Control Methods

Each QC method should be assessed by the repository or by the external laboratory performing the assays, for its accuracy and precision. Proficiency Testing programs using Reference Materials should be followed, when available, at least once a year (Schmehl, Bank and Cobb 1989; Day et al., 2007).

E6.100 Biological Safety

All human specimens and to a lesser extent animal specimens, whether fixed, paraffin-embedded, fresh frozen or freeze-dried should be considered as potential biohazards. As the extent of alteration of tissue increases (e.g., fresh to frozen to fixed to paraffin-embedded) the risk from various infective agents usually is reduced (Grizzle, Bell and Fredenburgh, 2005; Grizzle, Bell and Fredenburgh, 2010). However, certain agents such as prions [e.g., the causative agent for Creutzfeldt-Jakob disease (“mad cow disease”), scrapie, deer/elk wasting disease, or other transmissible spongiform encephalopathies (TSEs)] may still be infective even when tissues are fixed and processed to paraffin blocks. Consequently, all human and animal specimens independent of their state should be treated with universal precautions, i.e., should be handled as if infected with agents that may be pathogenic to humans. Individuals should receive training so that they can recognize symptoms that accompany the exposure to certain harmful compounds and diseases to which staff are exposed (Fleming and Hunt, 2006).

Facilities should develop a Bloodborne Pathogen Exposure Control Plan to eliminate or minimize occupational exposure to bloodborne pathogens. The plan should include a determination of employee exposure, methods to control exposure (e.g., universal precautions, personal protective equipment, engineering controls), appropriate vaccinations, post-exposure evaluation and follow-up, communication of hazards and accurate recordkeeping. Applicable regulations covering occupational exposure to bloodborne pathogens should be determined.

Best Practice: Risk assessment should be carried out to assure that all regulations are followed.

E6.200 Chemical Safety

Many countries have developed regulations that govern activities relating to chemical safety that may affect repositories (see Appendix A). These laws may mandate that an organization develop a written chemical hygiene plan. The chemical hygiene plan should be capable of protecting employees from hazardous chemicals in the laboratory and capable of keeping chemical exposures below the action level or in its absence the Permissible Exposure Limit (PEL).

All chemicals used in repositories should have material safety data sheets (MSDS) available for easy reference for employees who potentially will come into contact with the chemicals and auditors who will look for these documents. MSDS are available from manufacturers and should be provided either in hard-copy or from a provided URL for downloading.

E6.300 Electrical Safety

Electrical injuries can be avoided by ensuring that all equipment is properly grounded. Equipment should be tested for grounding when first purchased and yearly thereafter. Similarly, all electrical base plugs should be in good condition (grounding should be checked/verified) and electrical work should be done with great care ensuring that personnel in the affected work area are protected by removal of fuses and with written warnings at the fuse box. Also, care should be taken with electrical appliances/equipment around water sources in the repository/laboratory spaces, especially sinks. Electrical equipment should be unplugged prior to service, as appropriate, and staff should have visible control of the plug to avoid inadvertent energizing of the unit.

Mechanical storage units are rated to function at a specific voltage. Should the level drop below specified levels on board buck boosters will come on to stabilize the voltage. If conditions persist they can result in overheating of the wiring or components leading to failure or fire. Routine checks of facility voltages and/or noting of prolonged use of the buck boosters will alert staff to low voltage conditions.

Best Practice: Surge protectors or voltage regulators are recommended for stand-alone freezers if this is not part of the building electrical infrastructure.

Best Practice: All electrical equipment and base plugs should be tested for grounding.

E6.400 Fire Safety (See Section B8.000)

The local fire department or the organization's safety program can inspect a repository to evaluate fire safety prevention plans. Prior to such inspections and on a regular basis (e.g., annually), fire drills should be conducted, fire suppression equipment and safety showers/eye wash units should be tested, and emergency pathways should be posted at all room exits. Emergency exits should never be blocked, obstructed or locked and hallways should not be obstructed or cluttered. Flammable agents should be stored appropriately, including storage of large amounts of flammable agents in fire cabinets if more than several quarts are present in one area. Refrigerators/freezers that represent reduced dangers of causing combustion can be purchased for use in research laboratories. Smoking, if permitted at all, should be limited to designated external areas. Furniture, rugs, and equipment should be constructed of non-flammable material. Regulations for types of doors to serve as fire barriers should be followed as should fire requirements for construction of buildings that house specific activities (e.g., laboratories). Fire safety will be governed by national/federal, regional and local requirements. (See Internet sites in Appendix A.)

Best Practice: Fire safety should be an important component of an organization's safety plan.

E6.500 Physical Safety

The physical safety of employees should be considered in all repositories. Physical safety ranges from preventing falls to ensuring employees are not physically injured by other means. Ensuring physical safety involves careful maintenance of the physical plant and facilities, such as handling and/or prevention of tears in rugs, broken steps and water, soap, paraffin and other slippery substances on floors. Power cords should be appropriately covered, and inappropriate use of ladders or chairs as ladders should be prohibited to prevent falls. Similarly, unsecured gas cylinders, unbalanced file cabinets, and inadequately secured shelves all can lead to injuries via falling or moving agents or structures.

Also included in causes of physical injuries are repetitive-motion injuries (e.g., pipetting) and back injuries resulting from movement and inappropriate lifting. Repository staff members may be required to stand on step stools and lift heavy racks vertically out of the freezer in order to access specimens. Back injuries can be avoided by installing an automatic pulley mechanism to aid in the removal of the racks from the freezers. By analyzing an employee's work environment and improving the proper placement of objects and/or provision of the proper tools, the potential for injury will be reduced greatly. When ergonomics is applied correctly in the work environment, visual and musculoskeletal discomfort and fatigue are reduced significantly. Where feasible, repositories may consider automated specimen input and retrieval systems to reduce physical strain on technical staff.

Physical injuries that are difficult to avoid include minor cuts (e.g., paper), bumps and strains due to inattentive actions. However, such minor injuries should not be compounded by exposure to biohazards or chemical hazards. The overall safety program should address other hazards that can be prevented or ameliorated by wearing proper protective equipment and clothing such as the use of gloves to avoid thermal burns from both heat and cold (e.g., dry ice or liquid nitrogen). Check the occupational safety laws of your region (see Appendix A.)

For equipment that may be located within a confined space (e.g,. large robotic stores for DNA samples), procedures should be developed to assure that the equipment is not moved or operated during routine cleaning, maintenance, or repair.

Best Practice: Physical safety should be considered in an organization's safety plan.

E6.600 Radiological Safety

Few repositories will store or use radioactive material. For those repositories that do use radioactive material, a radiological safety plan is needed. Specific training is required for personnel who use or come into contact with radioactive material as well as in the use of specific radiation monitoring equipment. Work with radioactive materials in many countries requires a license from a federal regulatory committee. Repository staff should refer to the appropriate guidelines for the country or region in which the repository is located.

E6.700 Dry Ice Safety

Prolonged exposure to dry ice can cause severe skin damage through frostbite. Those working with dry ice in the laboratory should use appropriate protective wear approved for low temperatures. Dry ice sublimates into large quantities of carbon dioxide gas which could displace oxygen and pose a danger of asphyxiation. For this reason, dry ice is assigned the S-phrase S9 in the context of laboratory safety and should only be exposed to open air in a well-ventilated environment (Annex IV of European Union Directive 67/548/EEC: Safety advice concerning dangerous substances and preparations).

Although dry ice is not classified as a dangerous substance by the European Union or as a hazardous material by the Department of Transportation (DOT) for ground transportation, when shipped by air or water, it is regulated as a dangerous good and IATA packing instruction 904 (IATA PI 904) requires that it be labeled specifically with a diamond-shaped black-and white label with the UN 1845 designation. Arrangements must be in place to ensure adequate ventilation so that pressure build-up does not rupture the packaging (See Appendix A for internet resources). The monitoring of carbon dioxide levels for areas in which dry ice is used is recommended to ensure that the areas are safe for employees.

E6.800 Liquid Nitrogen Safety

At atmospheric pressure, liquid nitrogen (LN₂) boils at −196 °C (77K; −321 °F) and is a cryogenic fluid which can cause rapid freezing leading to cryogenic burns or frostbite. Cryogenic burns can also be caused by the contact of skin with substances cooled with liquid nitrogen (e.g., vials, hoses, storage racks).

Since the liquid to gas expansion ratio of LN₂ is 1:694, a tremendous amount of force can be generated if LN₂ is rapidly vaporized. As LN₂ evaporates it will reduce the oxygen concentration in the air and cause a potential risk of asphyxiation, especially in confined spaces. Nitrogen is odorless, colorless and tasteless, and may produce asphyxia without any sensation or prior warning.

Those working with or around LN₂ should use appropriate protective wear. A full face shield should be used to protect the eyes and face from splashes when working with large volumes of LN₂. Non-absorbent, insulated gloves (cryogenic gloves) should be worn when handling anything that is or has been in recent contact with LN₂. Cryogenic gloves are made to be used only in the vapor phase of LN₂ and should not be immersed in the liquid itself. A long-sleeved, buttoned lab coat should be worn at all times when working with LN₂ to protect the body. Non-absorbent cryogenic aprons can also be used and should be used when splashes may occur. Open pockets and turn-ups where liquid may collect should be avoided. Open-toed shoes should in no circumstances be worn when working with LN₂. Shoes should be sturdy and non-absorbent.

E6.900 Carbon Dioxide Safety

Carbon dioxide gas is a colorless, odorless non-flammable gas. In addition to presenting the risk of asphyxiation by displacing oxygen, carbon dioxide can present exposure risks such as changes in blood pressure, tinnitus, headache, irregular heartbeat, difficulty breathing, etc. While eye protection is not required for working with CO₂ gas it is recommended; however employees should wear oxygen monitors while handling CO₂ cylinders or working with CO₂ gas. Cylinders should be stored in well-ventilated areas in compliance with appropriate regulations.

F2.100 Training Program

Every individual who enters the repository for the purpose of performing work should be trained in the particular functions or tasks which they are asked to complete. Training should be task and location specific and be designed for the particular position that is expected to carry out the work. Training should involve instruction in the use of any equipment used and involve appropriate quality control and quality assurance practices.

Training for some functions may be provided by departments outside of the repository (e.g., maintenance staff, equipment vendors, infection control, professional air transport regulatory trainers) but repository staff should make sure that all individuals who enter the repository follow required safety and other policies in performing their particular tasks. Training must be in a language with which the employee is conversant and the level of training must be appropriate to the employee's level of comprehension.

Academic or other institutional training, in the form of courses, may be available by some institutions. The syllabus of such courses should be reviewed for correspondence with particular training needs and decisions made accordingly. Examples of areas covered by such courses may include legal aspects, management and financial aspects, cellular and molecular biology, statistical aspects, or quality assurance.

Repository staff should be asked to review any written procedures for which they are responsible prior to the commencement of their “hands-on” training. A written record indicating that the employee has read the pertinent procedures should be kept in the employee's training file (see Section F2.700, Training Records). This record should include the title of the procedure, the employee's initials, and the date upon which the procedure was read. It is preferable that a short test be administered to personnel concerning the material that is presented for the employee's review.

Best Practice: To ensure quality of repository activities, employee performance should be routinely monitored to identify needs for additional training between regular training intervals. Staff should be informed when first hired that routine monitoring of employees' performance is a part of regular practices for ensuring quality and is applicable to all repository staff.

F2.200 Trainers

The trainer is an employee who regularly performs the procedures in question, has completed the training program previously and is skilled in explaining the elements of the task. The trainer is responsible for assuring that the trainee understands each procedure and task. For special areas of training (e.g., human subjects protection, privacy, safety), personnel with special expertise may provide the training. Experts via audio-visual methods including web-based technologies may also provide training. This approach may permit employees to complete special areas of training at their own pace when time can be scheduled based on the employee's daily activities.

During the training period, the trainer demonstrates, explains and reviews the standards to be followed in conducting the procedure(s). The trainer should provide appropriate feedback, as necessary, on the trainee's performance of the procedure. The trainer should supervise the trainee in all tasks contained in the procedure(s) until the training phase has been completed. Upon successful completion of the training phase and after the appropriate documentation has been completed, the trainer should ask the trainee if they are comfortable conducting the procedure(s) without supervision or if they feel that additional training is needed.

Best Practice: After the training has been completed, the trainer should be available to answer questions when the task is being performed by the trainee for the first few times.

F2.300 Training Coordinator

Each repository should have an individual responsible for training who is responsible for all aspects of training. The individual maintains the SOP Manual and coordinates with the supervisor responsible for that particular procedure when any revisions are needed either due to the expiration of the SOP or for technical reasons.

The training coordinator closely coordinates issues related to training in safety with the organization's Safety Officer and with other individuals responsible for specific areas of repository procedures (e.g., shipping and handling).

The training coordinator is responsible for monitoring, training and maintaining appropriate training documentation of all employees. The training coordinator maintains records of employees to be trained in each required area, tracks the time of their periodic updates of training, informs the employees of potential times of training and ensures the training is completed according to the required timeframe.

The training coordinator closely coordinates documentation of training and educational activities with personnel who maintain employee records, as needed.

F2.400 Frequency of Training

Training and repeat training should be conducted in accordance with applicable regulations and also in accordance with the needs of the particular tasks and positions held by repository staff. In many countries, regulations require training before the employee begins working and yearly thereafter (e.g., biohazard and chemical hazard training). Training for regular repository tasks should be implemented before staff is asked to perform those particular tasks and repeat training should be performed according to a defined schedule described by SOPs. Supplemental training (sometimes in conjunction with “corrective actions” or a protocol change) may be required following the evaluation of particular incidents in order to prevent their recurrence or to enhance staff performance.

F2.500 Cross-Training

Repositories may find it advantageous to implement a system of cross-training. Cross-training is the practice in which staff is trained in a variety of procedures and individuals are able to perform each of these at any time requested. Cross-training alleviates staff burn-out, reduces staff turnover, offers opportunities for advancement and allows for coverage of key activities if staffing levels change either on a temporary or a permanent basis. Also, since some tasks require repetitive motion, cross-training may minimize physical strain among those performing those particular responsibilities.

F2.600 Training Documentation

Once the training is complete, a written record of the completed training should be made that includes the trainee's signature as well as the trainer's signature. Electronic signatures should be used for documentation of any electronic training that is received.

F2.700 Training Records

A training file should be maintained for each repository staff member and should include, but may not be limited to the following:

• Position description that includes the job title and responsibilities, as well as the educational experience required to perform the specified task.

The training file should be kept in the repository and be available for Quality Assurance or client review. The training file should be archived according to the repository's SOPs after the employee is separated from the organization. If an employee moves from the repository to another department within the organization, the employee's training file should be transferred to the new department.

I2.100 Specimen Location

Each freezer, refrigerator or room temperature storage cabinet should have a unique identifier. A convention should be established for numbering shelves, racks, boxes, as well as each location within the storage container. Each location combination (e.g., freezer, rack, box, row, and column) should uniquely identify a location in the repository. The inventory system should support different storage environments for the same repository and also should record the container type (e.g., vial, straw). The inventory system should be able to report on available storage space and able to assign and reserve space for incoming specimens.

To validate specimen location, a randomly generated specimen number/list or other appropriate randomized system should be checked on a subset of the samples on a regularly scheduled basis. This will ensure that the correct specimens are in the location specified by the inventory system (database). Certain storage systems (e.g., straws) are stored in containers such as goblets and the database should be able to capture such containers that do not follow the normal box/row/column configuration.

I2.200 Additional Specimen Descriptors

The inventory system should track specimen type; vial or container type; volume or size; date and time of specimen removal from donor, collection, receipt and/or processing; processing method; storage temperature; preservatives and any other characteristics needed for the collection. Information should be included on the history of sample processing and movement, including the location of shipments to and from external sites. Finally, any information about the sample being compromised in any way should be recorded and available to the user.

I2.300 Additional Information for Human Repositories

In addition to the information regarding specimen location, information relating to the following data may be maintained for a repository depending upon the nature, purpose and type of the resource (if relevant, available or not stored in another interoperable information management system):

• Donor information: Age of donor at the time of collection, sex, race, ethnicity, occupation, etc.

An inventory system may also be designed so that digitally scanned documents are included such as pathology reports, H&E slides of tissues collected, clinical lab reports, donor consent forms and material transfer agreements (MTAs, see Section M2.600, Material Transfer Agreements).

The information stored will vary according to the purpose, nature, and intended uses for the biospecimen collection. Since a repository may track samples of many different studies, consideration should be given to what the inventory database can contain and what should be stored in an external database and linked to the inventory.

I2.400 Additional Information for Non-Human Specimens

Many items listed in I2.300 can also be applied to the information tracked for non-human biological samples, specifically animal samples, as well as additional information not included above. The following information is important when collecting for animal/fungal/plant/microorganismal biobanks or environmental specimen banks (ESBs):

• Collection location: (latitude and longitude [and method of determination], altitude/depth, country/area/site/city, ocean/sea/bay, indoors/outdoors.

I2.500 Audit Trail

The inventory system should include a full audit trail of changes made to the database. This includes recording changes to both specimen data and system metadata. The audit trail should include but not be limited to: the original data; the changed data; who made the changes; how the change was made, date and time of change, and if possible, why the changes were made. This audit trail should be automatically recorded and available for read-only access.

Record changes should not obscure previously recorded information in the Audit Trail. Such audit trail documentation should be retained for a period at least as long as that required for the electronic records and should be available for agency review and copying.

I2.600 Security

Access to the computerized inventory system should be tightly controlled. Passwords should conform to the minimum institutional standards regarding password length, strength, life cycle, recycling, etc.

Security roles with defined privilege levels should be assigned to individual users of the system. Some individuals may be able to view specimen availability whereas others can enter or modify specimen descriptions and make requests to have specimens shipped from the repository.

The system should provide a mechanism to log off users after a specified period of time during which the system is idle.

All database access attempts should be logged with the date and time of login and logout. Any failures to access the database should be logged with the date and time and reason for failure. The system should lock out a user after a specified number of failed attempts to access the system.

The inventory system should provide for single system sign-on utilizing the operating system's user name and password if possible.

User authentication information should always be encrypted.

All remote communication should be able to be conducted on an encrypted socket (i.e., via a port that requires data encryption to prevent inappropriate access to secured data). For example, Web-based systems should be able to implement data encryption using a Secure Socket Layer (SSL) at the browser level.

All Protected Health Information (PHI) should be secured within the database through access controls and/or encryption.

I2.700 Interoperability

Within modern biorepository informatics systems, integration and interoperability are highly desirable. Systems should be able to integrate with other local applications such as electronic medical records, cancer registries, pathology systems and freezer temperature monitors. This allows other systems to be the single source of truth (SSoT) for appropriate data.

Integration and interoperability have many benefits which include, but are not limited to, the following:

• Reduced re-entry of data. Every time data is manually reentered from one system to another there is a risk of error. Re-entering of data can be costly.

Data should be electronically convertible into formats that can easily be shared among collaborating institutions, where possible and appropriate. The inventory management system should enforce all data integrity, security and audit trail requirements for external access. To achieve interoperability, inventory management systems should do the following:

• Have a public documented Application Programming Interface (API) to enable other systems to integrate with it.

I2.800 Reporting

The inventory system must have the ability to produce reports to support the repository workflow, document adherence to standards and practices and provide any business metrics required by the repository.

The system should provide the user with an interface for specifying display content and search criteria for the report. The exact nature of this interface can vary from full “what you see is what you get” (WYSIWYG) report designers to simple field selection for tabular reports. The query editor can also be presented utilizing several approaches, including simple data query forms, Query By Example (QBE) screens, customized query builders and text areas for native query specification.

The inventory system should have the ability to save reports for future execution. The inventory system should have the ability to generate report output and electronic data files (e.g., in ASCII, XML, or Excel format). The system should provide full access to the database for reporting, provided that the system's security rules are enforced. This access will allow users to generate reports on inventory status, freezer status, user access, audit trail entries, and other data tracked by the database to meet their needs.

If the database contains PHI records, the security model must restrict reporting on confidential data to only authorized users. Additionally, the repository should maintain SOPs about the generation, use, and destruction of reports that contain PHI to ensure that donor confidentiality is maintained.

I2.900 Validation

A closed system is defined as an environment in which system access is controlled by persons who are responsible for the content of electronic records that are in the system.

Persons who use closed systems to create, modify, maintain, or transmit electronic records should employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. Such procedures and controls should include the following:

• Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.

I2.1000 Quality Assurance

In order to provide high-quality information to serve the tracking system, standards, policies, and procedures should be used to ensure and maximize the quality, objectivity, utility and integrity of the data. Periodic reviews of data quality issues and adjustments to programs and processes will ensure continuous quality improvement. The electronic inventory system should comply with industry-applicable cGP guidelines (see Section D3.100, Current Good Practices). An established Quality Assurance program for the inventory system should be primarily directed at prevention of non-conformances as well as detection, corrective action and process improvement implementation.

Regular Quality Assurance audits and reviews should completely document:

• User requirements, as well as industry-specific certification requirements.

Best Practice: A periodic audit of the database should be performed to ensure accuracy of data.

I2.1100 Backup

Regularly scheduled backup procedures are an important security function that will enable the inventory system to be restored in the event original data is lost or corrupted, most typically due to drive or other hardware failures. The database should be backed up on a regular basis, depending on the institutional policies and frequency of data modification. The more frequent the data is changed, the more frequently the backups should be made.

The procedures to preserve the integrity of IT data should include (but are not limited to) steps to limit the extent of the destructive event, protocols for periodic backing up and storing of information, procedures for off-site storage of backup data, and protocols/procedures for restoring information from backed up media.

The procedures should specifically address the recoverability of information. Backups should be validated on a regular basis to ensure the data can be accurately recovered.

Changes to hardware and software commonly require review and reevaluation of these documented procedures. These procedures must specifically address the physical environment and equipment.

I3.100 Labels for Specimens

Human specimens should be labeled in such a way that protects privacy and confidentiality and is in compliance with applicable laws and institutional policies. Specimens should be labeled with a unique code or ID not derived from information about the donor. No other study or personal health information should be encoded in the specimen ID.

Best Practice: For all specimens, the repository's unique identifier for each specimen should be printed on the label in both barcode format and human readable form. The ID should not be reflective of its storage location in the repository, as locations may change over time.

I3.200 Barcoding

Whenever possible, labels should be printed with a barcode that uniquely identifies the specimen. Linear (1D) barcodes are adequate for small values and/or larger labels. Under some circumstances, two-dimensional (2D) barcodes are necessary. 2D barcodes have the advantage that scanning error rates may be lower, more information can be included on the label and they may be optimal for use on smaller vials. Some containers can be ordered preprinted, such as straws and small vials that fit in 96-position racks. In certain situations, preprinted containers can have an ID structure that alleviates applying another label onto the container and save supplies and labor.

Best Practice: Each aliquot or container should be labeled with a unique barcode/number.

J2.100 Regulatory Requirements

The shipper should first determine how to classify the specimens that are to be transported. Specimens routinely shipped from repositories such as infectious substances, diagnostic specimens, biological products, genetically modified organisms and microorganisms or toxic substances may be considered dangerous goods. Also, the preservatives that have been applied to the specimens may be considered toxic, flammable liquids, non-flammable gases, or corrosives, all of which are dangerous goods. In order to properly classify the specimens to be included in a shipment, one should consult their federal transport regulations as well as those from their International Civil Aviation Organization (ICAO) and IATA.

Many countries require that personnel involved in the transport of dangerous goods receive training in this area before they begin their shipping responsibilities. As regulations change, training may need to be updated.

J2.200 Temperature Requirements

Specimens may be exposed to temperature fluctuations during transit. Shipments of specimens with high value or those with critical temperature requirements should include a temperature-recording device that can verify the temperature of the material being shipped throughout the transport cycle. The following are typical temperature conditions required for transport of specimens and the insulation/refrigerant helpful to maintain that temperature:

• Ambient (20 to 30 °C) - insulated packaging to protect from extreme heat or cold ambient conditions.

Best Practice: Shipments of cold or frozen material should be shipped with sufficient and appropriate refrigerant to maintain temperature throughout the shipping cycle with allowance for at least a 24-hour delay in arrival time.

J2.300 Humidity Requirements

Specimens sensitive to humid conditions may need to be shipped in sealed bags with desiccant to prevent exposure to moisture during transit.

J2.400 Arrival Time Requirements

Time sensitive specimens such as fresh whole blood should be consigned to couriers with a proven reputation of successful on-time delivery. Time required for shipment processing should be considered as well. Shipments should be initiated when there are at least two working days left in the week, in case they do not arrive on the day scheduled for delivery. Shipments should also be scheduled so that they do not arrive at the recipient location on a holiday.

J2.500 Specimen Quantities

The quantity of specimens to be transported will affect the type of packaging and amount of refrigerant required to maintain appropriate temperatures for all specimens in the shipment. The container size should be appropriate for the amount of refrigerant needed and for the number of specimens that will be included in the container.

Best Practice: Shipments involving a large number of specimens should be divided into multiple, smaller shipments.

J2.600 Other Packaging Considerations

J3.100 Review of Packaging Test Report

The shipper is responsible for choosing appropriate packaging for the shipped material. The shipper should review all test reports for the packaging to ensure that the packaging regulations are met.

Packaging that has undergone stringency testing should be used in the same configuration under which it was tested. Tests may include measuring all parameters that could influence specimen integrity (i.e., temperature, humidity, light sensitivity, structural quality, and spill containment).

J3.200 Test Shipments

In some situations, especially relating to extremely valuable samples, repositories may choose to first send a test shipment that approximates the characteristics of the actual shipment. This may inform the shipper as to the adequacy of packing coolants and also serve to identify any potential obstacles for the successful shipment.

Best Practice: When test shipments (as well as subsequent specimen shipments) are performed it may be helpful to use a temperature-recording device or an irreversible temperature indicator during the shipment to ensure that temperature requirements have not been exceeded.

J3.300 International Shipments

Special permits or other requirements may be unique to certain countries and regions. Some countries have regulations related to ethical issues which prohibit the import/export of certain types of human specimens or have specific requirements concerning the import/export of such specimens. If collecting non-human biological samples that are endangered or protected, special permits such as the Convention on International Trade in Endangered Species of Wild Fauna and Flora permit, as well as additional paperwork may be required.

Most international shipments also require a customs clearance note to be clearly displayed on the outside of the package. Check with the country of delivery for the customs information that needs to be displayed. Identify all requirements for shipping to a designated country prior to the initiation of the shipment. Use of a customs broker can be helpful or even critical. Certain couriers can provide this service which can be essential for transport to/from a foreign country.

Best Practice: Due to possible delays in completing customs requirements, temperature sensitive material should be consigned with a courier capable of replenishing refrigerant in the event of a delay. As a precaution, three additional days' worth of refrigerant is recommended for shipments in cases where customs clearance may be difficult.

Best Practice: International shipments should include a letter on institutional letterhead (as appropriate) documenting the contents and handling requirements. Copies of all import permits and sanitary certificates should be included, as needed.

J4.100 Notification of Shipment

The shipper should notify the recipient that a shipment is scheduled to arrive on a specific date. The recipient should confirm that they are able to receive the package and that they have the proper facilities for storage before the shipper releases the shipment. The shipper should provide a 24-hour emergency contact for all packages transporting dangerous goods.

J4.200 Shipping Manifest

The shipper should send a shipping manifest (preferably electronic) to the recipient prior to the release of the shipment. A paper copy should also be included with the shipment itself.

J4.300 Confirmation of Receipt

Confirmation of receipt and the condition upon arrival should be documented for every delivery or shipment of specimens. A form that records this information should be sent with the shipment/delivery. Information as to how the condition report should be returned to the shipper should be clearly indicated.

K4.100 Biopreservation/Cryopreservation

Biopreservation is a general term used to describe the preservation of all types (e.g., viable and non-viable cells, blood, cell fractions, DNA) of biological materials using a range of low temperature and some ambient storage methods. Whereas, cryopreservation is a more specific form of preservation that involves the storage of cryoprotected living cells, tissues, organs and organisms at ultra-low temperatures, usually in LN₂ or its vapor to a minimum temperature of −196 °C. Cryopreservation involves the process of cooling cells or whole tissues to low sub-zero temperatures at which any biological activity, including the biochemical reactions that would lead to cell death, is effectively stopped. There are two distinct methods of cryopreservation: (1) preservation in the frozen state which can involve either ultra-rapid freezing (direct introduction into LN₂) or controlled-rate (slow programmable) cooling and (2) vitrification, which is preservation in the glassy, non-crystalline state. Both methods usually require the addition of cryoprotectants which have different protective properties (e.g., colligative or osmotic) although generally they will lower the freezing temperature. Cryoprotectants are applied in different regimes, combinations and concentrations dependent upon the mode of cryopreservation (e.g., frozen or vitrified).

Controlled-rate cooling minimizes the potential for lethal, intracellular ice forming during the freezing process; this is achieved by controlling extracellular ice nucleation (also termed ‘seeding’) and applying optimally slow cooling rates that allow sufficient water to leave the cell during the progressive freezing of the extracellular fluid. Controlled-rate cooling requires the careful control of cooling rate (e.g., around −1 °C/minute is appropriate for many mammalian cells), ice nucleation temperature and terminal freezing temperature and hold time (i.e., before specimens are transferred to LN₂); the optimization of which will vary between cells of differing size and water permeability. To circumvent cryoinjury caused by toxic cell volume changes and the excessive concentration of solutes the application of colligative cryoprotectants, such as DMSO, is required during controlled rate cooling.

In contrast, vitrification is a process that avoids the potential damage to cells caused by intracellular and extracellular ice formation. This is usually achieved by the addition of cryoprotectants at higher concentrations which increase the viscosity of the sample and prevent ice crystals from forming.

Common cryoprotectants, such as dimethyl sulfoxide (DMSO) are often toxic in high concentrations and care must be taken to limit the damage produced by the cryoprotectant itself. When possible, researchers should test available preservation solutions to determine what works best for their specific research activities and, as required, optimize the cryoprotectant strategy for their preserved samples. Using an appropriate cryopreservation media and cryoprotectant(s) will reduce the rate of degradation at hypothermic temperatures and offset the risks of inadvertent devitrification at ultra-low temperatures. When possible, researchers should test available preservation solutions to determine what works best for their specific research activities and, as required, optimize the cryoprotectant strategy of cryopreserved samples. Using an appropriate biopreservation media will reduce the rate of degradation at hypothermic temperatures and risks of inadvertent devitrification at ultra-low temperatures.

The temperature at which frozen and vitrified preparations are stored affects the length of time after which cells can be recovered in the viable state (generally, the lower the storage temperature, the longer the viable storage period). As temperature is reduced, metabolic and degradation processes in cells are slowed; however, they are not effectively slowed to allow for long-term storage (years to decades) until the temperature falls below the glass transition temperature of pure water (effectively <−132 °C for most mixtures of cells and aqueous cryopreservation media). The Tg of some vitrification solutions can be higher and it may be prudent to determine the actual critical Tg using thermal analyses. In addition to storage temperature, handling during removal from storage will affect the viability of cells and may result in degradation of cellular components. Every time a sample is warmed above the glass transition temperature, it experiences a micro-thaw event. Repeated thermal cycling episodes lead to increased cell death via apoptosis and necrosis. The temporal nature of delayed onset cell death resulting from preservation stress may affect the quality of data obtained from these samples depending on the timing of experiments post-preservation and the ability of the cells to recover from cryoinjury in the long-term.

K4.200 Freeze/Thaw and Cooling/Re-warming Cycles

Freeze/thaw cycles for specimens cryopreserved in the frozen state and cooling/re-warming cycles for specimens in the vitrified state can be damaging to the macromolecules and cells intended for analysis. Damage can also occur via osmotic and dehydration injury during exposure and removal of cryoprotective additives and vitrification treatments. Therefore, it is important to select aliquot sizes that are appropriate for the intended uses for the specimens in order to minimize the number of times a sample is thawed and frozen or vitrified before it is used. Samples are often maintained at liquid/vapor nitrogen temperatures in order to achieve biopreservation of the sample below the glass transition temperature (below which the cell biochemical activity is virtually stopped). Thermal cycling intervals resulting in sample temperature increase above the glass transition temperature allows for repeated freeze/thaw cycles even within the sub-zero frozen state. For these reasons it is essential to limit the potential of freeze/thaw and vitrification/devitrification cycles occurring when samples are introduced or removed from storage.

K6.100 Sterility

Risk assessments and mitigation exercises should be undertaken in the context of a specimen's requirements for asepsis. While complete sterile conditions may not be required for many specimen collections and processing, adequate consideration should be given to the cleanliness of instruments, surfaces and equipment used in specimen processing and handling. RNA is particularly sensitive to RNAses which may be present on tools and surfaces that have not been properly cleaned /sterilized. Where disposable instruments are used, every specimen should be handled with fresh new instruments and when non disposable instruments are used, they should be appropriately cleaned after each specimen processing. Sterility of preservatives, cryoprotectants and liquid nitrogen supplies should also be considered.

K7.100 Solid Tissues

Tissues may be collected prospectively, as a part of a population-based study, or for general purposes for future research activities. The collection of samples for research should never compromise the diagnostic and prognostic integrity of a specimen. This is especially important when human solid tissue specimens are collected during surgery and where pathology is involved in the subsequent diagnostic process. This is because attributes of the sample (e.g., the margin of the tumor or the number of tumor positive lymph nodes) may have a direct impact on the care that a patient subsequently receives (e.g., chemotherapeutic treatment vs. radiation therapy vs. no treatment).

The appropriate handling of tissues procured for research purposes is facilitated if a practicing pathologist supervises the actual procurement of the tissue; this is especially important to prevent the compromise of diagnostic specimens. Information from the pathologist on the characteristics of the biopsy or surgical material (e.g., % normal, % tumor, % necrosis and/or % fibrosis) should be recorded for future use so that the end user will be able to determine the usefulness of the tissue. Where possible, multiple sections or samples should be created to allow for greater use of the specimens.

K7.200 Blood Samples

One of the primary decisions in storing blood samples is whether to collect anticoagulated (plasma/buffy coat/RBC) whole blood or coagulated (serum/clot) blood. When serum is collected without anticoagulant, the blood clot obtained after processing can be used as a source of DNA for genotyping and other DNA related studies (Somiari et al., 2004). In similar fashion, blood collected with anticoagulant can yield a packed cell volume (containing both the buffy coat and RBC) to be used as a source of DNA.

When multiple blood collection devices/containers are involved there is a prescribed priority order of draw (see Appendix A for internet resources). The order of draw for clinical testing may be different from an investigator's requested order of draw. It is also important to determine which anticoagulants are acceptable for a particular downstream procedure. (See Section K5.000, SPECIMEN STABILITY).

Blood samples may be collected in different manners depending upon the amount of blood needed for a study and the distance between the sample source, processing location, and the repository. For example, blood samples may be collected at a location that is far away from the research site, in either small quantities as dried blood spots on treated or untreated matrices or collected in large quantities in tubes that provide stability at room temperature for several days.

Consideration should be given that cell viability and functionality from blood samples may be compromised during extended ambient storage/transport (Jansen et al., 2009); however new technologies have been developed to significantly extend ambient storage/transport of blood samples for up to 1 year (Wilkinson, et al. 2011). Hypothermic temperatures (2–8 °C) may allow for extended stability of blood-derived cell products.

Best Practice: Blood samples should be processed and stored within four to twenty-four hours of draw, depending on the analytical endpoints (Tuck et al., 2009.)

K7.300 Urine Samples

Urine samples should be maintained on ice or refrigerated after collection. Collection containers should be sterile and dry, and have a 50 mL to 3 L capacity, a wide mouth, and a leak-proof cap. Depending upon the analyte to be measured, a preservative may be needed. The type of preservative may differ according to test methodologies, time delay and transport conditions. EDTA and sodium metabisulfite are examples of preservatives commonly used in urine collections. Urine containers used for environmental toxicology assays should be high density polypropylene to minimize phthalate contamination. Because urine may contain cellular and other elements, a urine sample is typically centrifuged to remove cells and debris. The acellular urine and separate cell pellet can then be analyzed and/or frozen as aliquots.

There are various methods of collection (e.g., first morning urine, random, fractional, timed) depending on the type of analysis intended. The collection method should be documented in the sample record.

K7.400 Nail and Hair Clippings

Nail and hair clippings can be used for trace metal analysis to provide a longer-term measure of exposure. These samples are simple to collect, store and ship. They can also be used as a source of DNA.

K7.500 Saliva and Buccal Cell Samples

Saliva samples are used for drug testing, HIV detection or monitoring of hormone levels and as a source of DNA. Collection devices for these specimens include non-covered cotton roll, polypropylene-covered polyether roll and paraffin wax chewing stimulation. Some researchers may request donors to provide saliva samples directly into a container with an opening large enough to facilitate this collection. Saliva can be stored either as non-centrifuged aliquots or centrifuged, which results in supernatant and pellet aliquots which can then be analyzed and/or stored separately.

Buccal cell specimens may be useful as a source of DNA. A variety of collection techniques and containers have been developed specially for these collections. See references for several of these in Appendix A.

K7.600 Breast Milk Samples

Breast milk collection can be initiated when breast-feeding starts. Breast milk can be collected by manual expression or vacuum pump and should be collected in autoclaved or specially cleaned bottles and are typically stored frozen. If certain analytes such as phthalates are of interest, the sample can be collected in a glass bottle with Teflon™ cap and stored in the participant's household freezer.

K7.700 Stool Samples

Samples are self-collected by participant into a container that can be lined with plastic wrap or placed inside another container to provide an impervious storage container. After collection the sample should be frozen. Some procedures will allow for lyophilizing the sample for long-term storage which provides a more inert (less odoriferous), smaller sample for analysis.

K7.800 Cervical Vaginal Lavage Samples

Cervical vaginal lavages (CVL) can be obtained and used for HPV studies.

K8.100 Locating Specimens in Storage

The location of specimens to be retrieved should first be verified in the appropriate specimen inventory system (Section I2.000, Inventory Systems). A specimen requisition is generated according to procedures applicable to the repository's specimen requesting, tracking and inventory protocols. The requisition is checked for accuracy before transmission to the repository, according to established SOPs (see Section D2.220, Critical Topics for Manuals Containing SOPs) and QC standards (see Section D3.000, Quality Standards).

K8.200 Specimen Retrieval

Specimens should be located and pulled from storage as documented on specimen requisition forms. If specimens are frozen or vitrified, speed is necessary during the retrieval process. Such speed may require that at least two individuals carry out the retrieval process. If possible, specimens being retrieved should be maintained at the storage temperature throughout the process (e.g., specimens stored at −80 °C should be kept on dry ice during the retrieval process). Forceps may be used when withdrawing specimens stored at LN₂ temperatures to prevent warming of the specimens from contact with hands.

Once retrieved, staff should confirm that all requisitioned specimens have been accounted for. Quality control checks should be performed to confirm that all specimens listed on the requisition were retrieved.

If specimens appear to be missing, protocols should be followed in order to locate the missing specimens. Inventory systems should be updated to indicate that samples are in fact missing or that they were improperly located when placed in the inventory.

Best Practice: A second, independent quality control check should be performed to ensure that the correct specimens have been retrieved.

Best Practice: Mechanisms should be established to track before the last aliquot of a critical material is about to be used.

K8.300 Thawing, Re-warming and Aliquoting Specimens

L2.100 Human Subjects Review Board/Ethics Review Committee

A human subjects review board (institutional review board or ethics review committee) is any board, committee, or other group formally designated by an institution to review biomedical research involving humans, to approve the initiation of the research and conduct periodic review of such research. As a component of a human subjects/ethics review, the processes and procedures for collection, storage, distribution, and use of human specimens for research should be evaluated to ensure that these procedures are appropriate to protect human subjects.

L2.200 Informed Consent

Informed consent for the collection, retention and use of specimens is a process that offers donors information sufficient to allow them to make an informed choice about whether to provide specimens and data to the repository and agree, where applicable, to future research use. Consent should only be obtained under circumstances that provide the prospective donor or the donor's representative sufficient opportunity to consider whether or not to participate and minimizes the possibility of coercion or undue influence. The information that is given to the donor or the representative should be understandable to the subject or their representative.

Consent may be obtained for a specific research project, such that the details of the project can be specifically outlined. Alternatively, consent may be obtained for unspecified future research, in which case general information about the possible future research uses are provided, in accordance with applicable national or local regulations and policies. Mechanisms should be in place to assure that future research uses of specimens are consistent with the original consent (e.g., through review by a human subjects/ethics review committee or other mechanisms consistent with applicable regulations and guidelines).

Donors should have the right to withdraw consent and to have their unused specimens and data removed from the repository unless the specimens and associated phenotypic or demographic data are anonymous and cannot be linked by the repository to donor identities. The conditions under which a donor may make this request as well as the logistics for how a donor initiates this request should be specifically outlined in the informed consent document and process.

Best Practice: Donor consent should be obtained unless waived by an authorized human subjects/ethics committee constituted in accordance with applicable laws or regulations.

L2.300 Protection from Research Risks

Care should be taken to minimize the risks to subjects, and ensure that risks do not outweigh the benefits of the expected findings from studies using the specimens. This includes minimizing physical risks and psychosocial risks associated with the collection of specimens and/or data and ensuring that the collection of specimens and data does not affect patient care.

The repository should follow well-documented procedures to protect the privacy and confidentiality of the donors from whom the specimens and/or data are obtained. Such procedures may include: completely anonymizing specimens and data; assigning a unique code and/or removing all identifying information from the specimens and data; storing specimens and data securely; restricting access to specimens and/or data; and providing firewalls between the subject identity and the recipient investigator. Such firewalls prevent inappropriate data from passing in either direction through the firewall (e.g., identifying information to the researcher or specific research results that have not been validated to the donor). In addition, identifying information should be removed before allowing the recipient investigator to have access to specimens and/or data, unless the investigator has human subjects/ethics committee approval to have access to this information.

Best Practice: The collection of specimens and/or data for research must never adversely affect patient care.

Best Practice: Every effort should be made to protect the privacy and confidentiality of data associated with the specimens.

L2.400 Specimens Obtained from Mentally Impaired Persons

Extra care and attention should be given to the consent process when donors are incapable of signing the consent form themselves. Patients in this group would include those under heavy sedation, patients with dementia, or patients with syndromes of impaired consciousness, such as coma, brain death, locked in syndrome, and persistent vegetative state. Ethical guidelines for the management of patients in these conditions have been published by the British Medical Association (1996) and the American Neurological Association Council on Ethical and Judicial Affairs (1999). In cases of demented or mentally incompetent donors, a relative or legally authorized person could sign the consent form on the donor's behalf. In some countries, the donor must be informed regardless of their age, medical, or mental condition.

L2.500 Specimens Obtained from Autopsies

Biospecimens may also be obtained during autopsy from pathologists at hospitals, institutions, or the coroner's office. Full consent or authorization should be obtained from the donor (e.g., a signed agreement to donate their body for scientific research), the next of kin, or a legally authorized person. In the U.S., some states require consent from the next of kin even if the consent was obtained from the donor prior to death. It is important to rapidly harvest organs and tissues soon after the donor has deceased (i.e., a “rapid autopsy”), since mRNA and many proteins are sensitive to enzymatic degradation.

European countries have adopted legal frameworks in order to improve the accrual of tissues for research from autopsies. An ‘‘opting in’’ system has been devised whereby potential donors must register in advance. Alternatively, an ‘‘opting out’’ system has been developed, in which it is presumed that people give their consent for donation unless they register their objection (Jacob, 2006).

L2.600 Specimens to be used for Genetic Analyses

Some repositories either use a “tiered consent” form (one that allows participants to consent to some aspects of the research but not others) or require a separate consent form to be signed by donors when their biospecimens may be used for genetic testing or for mutation analysis. When genetic information generated from biospecimens is stored in a database, it is important that confidentiality is maintained and that the database server is secure. In some cases, national standards have been set for such security. Complex ethical issues arise when genetic testing is performed on biospecimens, such as whether to inform donors of their research results, whether to inform donors' families when heritable genetic factors are identified in tissues, especially post-mortem tissues, whether to inform families about possible disease risks, whether to ask relatives to collaborate on heritable genetic testing, and whether to advise relatives to seek genetic counseling. These ethical issues are currently unresolved and are especially difficult if there is no known treatment or cure for the disease at hand. Furthermore, in some jurisdictions there are laws that prohibit the return of results unless conducted in an approved laboratory. Even then, the results or their interpretation may be incorrect and their use in medical decisions might cause harm to patients. Thus, it is essential to discuss these issues with the human subjects/ethics review committee during the design of a repository protocol and informed consent and before returning any research results to subjects, their families, or physicians.

L2.700 Consideration of Perspectives of Communities, Populations, Ethnic and Social Groups

In some cases, there may be risks to ethnic and social groups or communities due to the release of aggregate research findings even when no individually identifiable information has been revealed. In addition, some populations or groups have specific beliefs about the disposition and use of their specimens, which should be respected.

Best Practice: When research focuses on a particular community it is best to seek input from representatives of the group on relevant aspects of the design of the study, the consent process, appropriate uses of specimens and dissemination of collective research findings.

L2.800 Special Considerations for Collection of Pediatric Human Biospecimens

L5.100 Termination of Repositories

Repositories should develop plans at the time of their establishment for the disposition of specimens and/or data should the repository be terminated for any reason. The disposition, including any transfer of specimens and/or data to third parties, should be consistent with the informed consent under which specimens and/or data were obtained.

L5.200 Ethical Disposal of Biospecimens

For some populations, disposal of biospecimens may have ethical considerations. Depending upon the nature of the study population and the repository, repositories and recipient researchers may be required to dispose of unused specimens according to local, legal, ethical and safety rules for the disposal of human remains. Alternatively, recipient researchers may be requested to return unused specimens to the repository.

M2.100 Access and Use Policies

Repositories should have well-established written policies for sharing and distributing specimens as well as procedures for determining what constitutes appropriate research use of the specimens and data.

Access policies should be in compliance with existing rules, regulations, policies and applicable laws. When investigators are required to obtain human subjects or ethics committee review and approval for the research use of specimens and/or data, documentation of such approval should be obtained prior to specimen or data distribution.

Best Practice: Human specimens and associated data should be distributed without information that could identify the donor, unless identification is absolutely necessary and the human subjects or ethics committee review has granted permission for inclusion of identifying information.

M2.200 Review of Specimen Use Requests

Requests for specimen use should undergo some level of scientific and/or administrative review to ensure proper utilization. Considerations may include scientific merit and potential impact of the proposed research, whether the research use is appropriate to the nature and purpose of the repository, availability of specimens of a specific type, adequacy of the research design and funding, public health benefits and risks of the proposed research, legal and ethical considerations and qualifications of the research team and research environment. Review should also consider requests for studies requiring rare specimens, specimens annotated with large amounts of data and those that require additional processing, pre-analysis or special handling by the repository staff.

Best Practice: Use of specimens and associated data should be consistent with informed consent and authorization.

Best Practice: Biospecimen resources should have a well-documented and clearly defined process for sharing specimens and data, prioritizing requests for access to specimens and data with limited availability and a mechanism for evaluating competing requests for scarce resources. Requests should be reviewed in a timely manner by qualified individuals.

M2.300 Data Sharing

M2.400 Benefit Sharing

Benefit sharing is another important consideration, particularly when dealing with specimens or data from developing countries. Sharing the "benefits" from specimen research is important to ensure that providers of resources are treated in a fair and equitable way. The concept of benefit-sharing grew out of discussions about developing countries profiting from plant and animal materials collected in developing countries without benefit to those who provided the raw material. An international protocol, the Convention on Biodiversity was signed by 150 countries. How the concept applies to specimen research is not always clear, but certainly involves avoiding exploitation (e.g., in developing countries). There are numerous ways that "benefits" can be shared. These include sharing of technology or sharing benefits of research with the study population or providing security backup of stored specimens in an established repository with quality practices in place. Some countries (e.g., India) only allow specimens to leave the country for research purposes if a collaborating investigator from the country accompanies them and participates in the research. This practice may promote technology transfer and development of local research infrastructure.

Best Practice: The repository procedures for collection, storage, distribution, use and disposal of specimens should respect the perspectives and traditions of donors from whom the specimens were obtained and minimize the risks to communities, populations, and groups.

Best Practice: Repositories that import specimens and data from other countries should respect the autonomy of the providing country and ensure that fair and equitable benefits are made available to the providing country.

M2.500 Publishing and Provision of Data to Repositories

In publications that result from the use of specimens, the repository should be acknowledged as the source of the specimens. Prior to providing the specimens, authorship guidelines should be established, so that it is clearly delineated between those cases when the repository is merely serving as a source of specimens and those cases when repository staff members actively participate in the research project itself, and therefore should be considered co-authors (e.g., by providing substantial intellectual input beyond the routine role of the repository, which may include data analysis or manuscript preparation).

Many repositories are required to provide an annual report to funding agencies that describes the outcome of the studies that recipient researchers have performed with biospecimens. For this reason, recipient researchers may be requested to provide the repository with a listing of abstracts, presentations, publications, patent applications, and funding that has been the direct result of using specimens from the repository.

Some repositories may ask specimen recipients to provide research data on individual specimens to the repository (either aggregate findings or individual-level data). The desired data format can range from the abstract of any publication based on analysis of the materials to the publication itself, a data summary, or the complete experimental data set. Repositories may also request a description of analytical methods used to generate or process the data, including quality control measures. The provision of such data may enhance the value of repositories, depending upon their purpose and nature. Consideration of a data provision policy is recommended, particularly when significant specimen-specific data is available. Repository administrators should consider whether the repository's purpose would be served by retrieving data generated through analysis of shared materials.

The repository's intended use of data will influence other aspects of its data acquisition practices. Repositories may ask researchers to provide the repository with data derived from individual samples or aggregate research results for a variety of reasons including:

• To document repository value and accomplishments.

Repositories may specify a date by which sample recipients should or must provide data. A standard date may be set (e.g., 12 months after publication or completion of the research), or a date may be set by project. Sample recipients often require time following the completion of research activity for publication of results or for securing intellectual property rights before data can be provided to a repository.

Best Practice: When biospecimens are used in research publications, care must be taken to ensure donor confidentiality. In most cases, de-identified biospecimens are provided to recipient investigators such that coded numbers fully protect the privacy of the donors.

M2.600 Material Transfer Agreement

A Material Transfer Agreement (MTA) is a contract that governs the transfer of tangible research materials between two organizations, a provider and a recipient, when the recipient intends to use it for his or her own research purposes. The MTA defines the rights of the provider and the recipient with respect to the materials and any derivatives. Biological materials such as specimens, reagents, cell lines, plasmids and vectors, are the most frequently transferred materials, but MTAs may also be used for other types of materials, such as chemical compounds and even some types of software.

Other types of agreements without the title of MTA may be used, but generally would serve the same purpose and have the same components as an MTA.

M3.100 Specimen Destruction

There are a number of circumstances that may influence decisions as to whether or not a collection should be destroyed. Some of the reasons for destroying samples may include:

• When all identifying information has been lost.

Best Practice: A repository should assess and document the destruction of any samples, noting when they are destroyed and for what reason. This information can be important to the repository's quality management and may serve as an indicator for the repository of areas that need improvement.