Laboratories are increasingly collecting biological samples, or biosamples, in formal repositories for use in research, driven in part by the availability of new analytic methods in genomics and proteomics. Biological repositories are distinguished from simple collections of biosamples by many features, but most prominently by the fact that biosamples in repositories may be used multiple times by multiple users over the course of an extended period of time. The establishment of a repository requires careful consideration of factors, such as what type of biosamples will be stored and how they will be collected, processed, stored, and retrieved. Although no national standards exist for tissue repositories, a number of organizations, such as the International Society of Biological and Environmental Repositories (ISBER), The National Committee for Clinical Laboratory Standards (NCCLS), and RAND Corp. have been developing guidelines and best practices for the management of repositories. These repository references are listed in Table 1.
Table 1 - Best practices for repository resources
As the number of biosamples in repositories inexorably continues to increase, the use of automation and information systems to manage and track them becomes increasingly important. This application note highlights best practices for the management of biosamples in archives with a focus on how automation and information technology infrastructure can assist in fulfilling organizational, ethical, and operational infrastructure requirements. Where relevant, the features of the DYNAMIC ARCHIVE® (GenVault, Carlsbad, CA), an integrated biosample management system, and the ways in which it assists its users in meeting such best practices, are described.
Repositories should have a designated individual who is clearly responsible for its operation, such as a laboratory director or research principal investigator. This individual is in turn responsible for hiring, training, and leading the personnel responsible for the daily management of the biosamples. An organizational chart and files documenting each individual’s training and specific responsibilities should be maintained in an archive whose access is limited to designated archivists. In general, these requirements follow those found in the FDA’s Good Laboratory Practices for preclinical studies.
These organizational requirements are intended to ensure that only individuals with proper training and authority carry out specific actions in a repository. Sample or laboratory information management systems (SIMS or LIMS) can assist in this area through the use of authentication and role-based authorization. For example, a technician who enters his/her user name and password (authentication) may be allowed to apply blood biosamples to plates, but may not be qualified to view or annotate clinical data associated with biosamples (restricted role-based authorization). Ideally, the SIMS should allow for flexible configuration of roles, since roles vary among settings and over time.
DYNAMIC ARCHIVE software enables laboratory managers to assign multiple individuals access to configurable roles in a repository. In addition, it allows individuals to be assigned to multiple roles if necessary and allows administrators to manage lists of employees assigned to various roles. Finally, permanent audit trails allow the retracing of actions performed by individuals within the software. These are all key features that assist groups in achieving compliance with 21 CFR Part 11 regulations covering electronic records and electronic signatures for electronic data submitted to the FDA.
Legal and ethical infrastructure
It is imperative that biological repositories operate according to appropriate legal and ethical standards to protect the privacy and wishes of biosample donors. As defined in 45 CFR 46, federally funded laboratories are required to follow Human Subjects Regulations, which are de facto ethical standards that should be followed by all repositories. In general, the regulations require that biosamples be collected and stored using proper informed consent in studies that have been reviewed by Institutional Review Boards (IRBs). They also require that biosamples be distributed only to researchers who plan to conduct a study that has been approved by or is exempt from an IRB review. The identifiers that are retained with biosamples and access to those identifiers are often the focus of IRB review, since the main threat to participants is often unauthorized disclosure of identity and sensitive medical information.
The ethics and regulations surrounding the use of biosamples can become quite complicated and are often dependent on local regulations and the context of the use of the biosamples. This is particularly true when samples are to be reused in multiple research studies. Indeed, in this area, various federal regulations are often not completely consistent, although work is in progress to reconcile and unify these regulations. A list of these regulations and ethical guidelines is provided in Table 2.
Table 2 - Repository regulations and ethical guidelines
It is thus a best practice to have the policies and practices of a repository reviewed and approved by an independent IRB. Important components to be reviewed are privacy and security policies that will be read, signed, and followed by all repository employees. In addition to following ethical standards, it is also a best practice to clearly define the intellectual property rights regarding biosamples that are distributed. This is typically managed through material transfer agreements signed by recipients of the biosamples.
Integrated biosample management systems can assist in ensuring that biosamples are collected and distributed in an ethical and legal manner through the use of predefined role-based authorization and work flows. For example, DYNAMIC ARCHIVE software requires that biosamples be assigned to a specific study. For each study, only designated individuals may request biosamples, and only individuals with Study Administrator roles have the ability to approve requests for biosamples to be distributed out of the DYNAMIC ARCHIVE.
Biosamples collected in a repository are valuable only if they are collected, processed, stored, and retrieved in a consistent and high-quality manner. It is thus a best practice to establish standard operating procedures (SOPs) for all operations, equipment, and reagents used in a biological repository. All procedures in a laboratory should be readily available to personnel, and documentation of training and understanding of procedures should be maintained for all employees. Specific aspects of repository operations requiring SOPs are discussed in detail below.
Biosample collection, packaging, and shipping
Biosample collection is a critical first step in the procurement of material for a repository. A detailed SOP should be developed to clearly define a protocol and all the parameters required, which will vary according to the type of biosample being collected. A best practice is to employ a systematic identification system, such as a bar-code system, to label the biosample upon collection to enable accurate downstream tracking of it. Typically, biosamples are collected using kits that have been prelabeled and prepackaged for use in the field.
Figure 1 - Each GenPlate incorporates a unique biological bar code, GenCode, which is embedded within each element. GenCode permanently links each GenPlate and the associated biological sample throughout all downstream genetic analysis. GenCode can be decoded by a series of multiplexed amplification reactions followed by gel electrophoresis to visualize its unique pattern. This pattern is decoded by a simple binary algorithm that allows GenVault to link each GenCode with the physical bar code on the originating GenPlate.
Biosamples are most often collected in locations that are physically separate and distant from where they are stored. It is thus a best practice to standardize methods by which biosamples are packaged and shipped to the ultimate storage location. Details such as ambient shipping temperature and duration of transport can be critical to maintaining the biological integrity of a biosample and the validity of its downstream analysis. Liquid biosamples are also likely to be subject to International Air Transport Association (IATA) regulations governing the shipment of hazardous materials.
The DYNAMIC ARCHIVE system is designed to simplify collection and transportation procedures through the use of standardized 384-well GenPlates. Each well contains an FTA (Fast Technology for Analysis, developed by Flinders Technology Association, Australia) paper element to which whole blood or DNA may be applied and dried for permanent storage. Dry-state storage of whole blood or DNA allows for the collection, transport, and storage of biosamples at room temperature. In addition, bacteria and viruses are inactivated by FTA, allowing the shipment of GenPlates using standard courier packaging. For identification purposes, a combination of oligonucleotides, GenCode, is applied to each of the 384 FTA elements in a GenPlate. PCR and agarose gel electrophoresis may be subsequently employed to “decode” the GenCode, which corresponds to a physical bar-code label on the GenPlate and ensures fail-safe identification of biosamples throughout analysis (Figure 1).