COMPLIANCE & GxPs COMPREHENSIVE SAMPLE MANAGEMENT THE FOUNDATION OF DRUG DEVELOPMENT Maximizing the potential of biospecimens for current and future drug development by ensuring their long‑term integrity through best practices, regulatory mandates and preparation techniques. G iven the significant role of biospecimens in drug development, it has become essential for pharmaceutical and biotech companies to develop a comprehensive strategy for the preservation of collected biological samples. The value of these materials (tissue, DNA, RNA, plasma and so on) is rapidly increasing because of discoveries that can be made from both prospective studies and retrospective analyses. These invaluable and sometimes irreplaceable materials represent assets that can bring significant long‑term commercial and scientific value to an organization. Companies are, therefore, collecting a growing amount of patient samples during clinical research; in fact, there are currently more than a billion samples stored in research labs and biorepositories worldwide.1 These samples are used to spearhead various initiatives, including a variety of testing, auditing, validation and qualification processes on collected specimens to: • Detect new biomarkers. • Identify biological and genetic factors responsible for different drug responses across individuals or populations. • Reduce the time it takes to bring new drugs to market, thus maintaining a competitive advantage. • Expedite R&D processes for new pharmaceuticals and therapeutics. Because of the intrinsic value of these materials, preserving clinical specimens to the highest of standards has become a critical component of the drug development process. Biospecimen Sample Collection and Preparation Pre-analytical variables introduced during clinical sample collection and processing can significantly affect the molecular integrity of specimens and bias the results of assays and/or biomarker studies. An essential component of any sample management strategy, therefore, requires standardized protocols for sample collection and preparation techniques. Biospecimen collection involves three components: collection of the sample, processing of the sample and recording of information about the sample. Information about the sample is of three types: its source (study subject), its characteristics (skin tissue plug biopsy) and its post‑collection processing and storage (for example, 38 www.pharma-mag.com placement in freezer 10 min after collection).2 For example, the time elapsed in each step from collection through storage should be recorded and tracked to ensure a consistent process and to possibly explain anomalies. Unrecorded information could be unrecoverable, which could exclude usage of a valuable time point, data point and/or disease state. This omission could inhibit discovery, as future uses of a sample often cannot be anticipated. Sample preparation methods may also affect the results or interpretation of biological studies. Inexact sample preparation can lead to sample loss, reprocessing or complicated data interpretation. This bottleneck can delay studies, which ultimately delays a potential drug candidate from going to market. Logistical Challenges in Specimen Management With the globalization of clinical research, the safe, punctual and compliant transport of biospecimens for testing and analysis is ever increasing in complexity and critical to the sample management process. The strict temperature constraints placed on these materials makes their timely distribution particularly important. Cold chain management defines how specimens, such as tissue, blood and DNA, are packaged and transported throughout the research and development process. Weakness or failure at any point in the chain of custody can compromise product integrity, breach security, delay shipments and ultimately result in financial loss or liability. Common issues that can affect biospecimen integrity during transport include: • Prolonged delivery delays caused by transportation glitches, security inspections or customs scrutiny. • Temperature fluctuations whilst in transit inside shipping vehicles. • Seasonal or climatic differences between origination site and destination. To mitigate risk of material degradation and ensure regulatory standards are upheld, personnel should understand the intricacies involved in transporting biospecimens on a global scale. The US Department of Transportation and the International Air Transport Association (IATA) require organizations and individuals who ship or receive biological materials to undergo formal training to meet their standards in packaging, labeling, documentation, declaration, September/October 2011 COMPLIANCE & GxPs Section Details B4.000 — RECORD RETENTION Unless otherwise specified by contract, corporate or government policy or other agreement, each repository should establish a period of time during which all records are retained. A policy should be in place for the destruction or return of records that no longer need to be retained. E2.000 — QUALITY ASSURANCE PROGRAMME Each repository should have a Quality Assurance Programme/Quality Management System (QA/QMS) or adhere to the QA programme of the organization with which the repository is associated. The programme should describe the repository’s commitment to its QA and QC programmes and describe approaches for ensuring that the requirements of the QA and QC programmes are met. H2.000 — LABELS Each specimen container should receive a computer‑printed label that tightly adheres under all projected storage conditions. Information encoded on labels should be resistant to all common laboratory solvents. Labels should include readable indications as to what is stored in the container. I3.200 — VERIFICATION OF PACKAGING Packaging should be tested prior to use with specimens. Tests should include measuring all parameters that could influence specimen integrity (that is, temperature, humidity, light sensitivity, structural quality and spill containment). J4.100 — FREEZE/THAW CYCLES Freeze/thaw cycles can be deleterious to the macromolecules intended for analysis. Therefore, it is important to select aliquot sizes that are appropriate for the intended uses for the specimens to minimize the number of times a sample is thawed and frozen before it is used. J9.200 — SPECIMEN RETRIEVAL Specimens should be located and pulled from storage as documented on specimen requisition forms. If specimens are frozen, 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 (for example, specimens stored at −80 °C should be kept on dry ice during the retrieval process). K2.200 — INFORMED CONSENT 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 is provided, in accordance with applicable national or local regulations and policies. Mechanisms should be in place to assure that future research uses of identifiable specimens are consistent with the original consent (e.g., through an IRB, ethics committee review or other mechanisms consistent with applicable regulations and guidelines). K2.600 — TERMINATION OF SPECIMEN RESOURCES Specimen resources should develop plans at the time of their establishment for the disposition of specimens and/or data should the resource 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. A.200 — SPECIMEN ACQUISITION, ACCESS AND CULLING Policies should be established for the acquisition of new specimens, access to specimens for research purposes, for culling of collections when specimen resources have fulfilled their original purpose or are no longer suitable for their intended purpose, or if participants request the withdrawal of their specimens. Table I: ISBER best practices for the collection, storage, retrieval and distribution of biological materials for research. Source: 2008 Best Practices for Repositories: Collection, Storage, Retrieval and Distribution of Biological Materials for Research hazard assessment and emergency response. Aside from the regulations, improper packaging and handling are common causes of temperature deviations. Proper training and qualification of all cold chain partners minimizes such problems. Regulations and Customs Agencies The US Department of Transportation Hazardous Materials Regulations (HMR) and IATA Dangerous Goods Regulations (DGR), along with other country‑specific regulations, specify requirements for the safe transportation of hazardous materials by railway carriage, aircraft, shipping vessel and motor vehicles.3,4 These regulations dictate specifications for classification, packaging, hazard communication, shipping papers, incident reporting, September/October 2011 handling, loading, unloading, segregation and movement of hazardous materials. Fines and shipping delays often result from lack of compliance with these regulations. Customs regulations in emerging regions are also complex and strictly followed by informed local Customs agents. Any issues with the shipment itself, or the accompanying paperwork, can result in material being held by various government authorities for prolonged periods. With the current growth in temperature‑sensitive products and time‑sensitive shipments, developing a strategy, including contingency plans, to avoid these issues is essential. For example, when materials face possible delays during the clearance process at Customs, consigning shipments with a courier who is capable of replenishing refrigerant, such as dry ice, whilst awaiting clearance may be difficult. www.pharma-mag.com 39 COMPLIANCE & GxPs Rigorous demands from authorities and industry associations worldwide necessitate that standard operating procedures (SOPs) be set in place not only for shipping, but also for labeling and documentation. Any controlled transport storage conditions, as well as warning statements or content identification, should be clearly stated on the label applied to shipping containers. Labeling and packaging must comply with IATA guidelines, be securely attached and clearly state that materials are to be transferred to a specified storage temperature upon receipt. Specimen Storage: Good Storage Practices Lori Ball Chief Operating Officer BioStorage Technologies, Inc. References 1. w ww.labmanager. com/?articles.view/ articleNo/3455/ 2. http://firstclinical.com/ journal/2011/1101_ Biostorage.pdf 3. w ww.phmsa.dot.gov/ staticfiles/PHMSA/ DownloadableFiles/Files/ Overview%20of%20 HMR.pdf 4. w ww.iata.org/Site CollectionDocuments/ 51NoticeUN3373Dec09.pdf 5. w ww.isber.org/bp/ BestPractices2008.pdf 6. www.biomedcentral. com/1471-2407/9/409 For more information Lori Ball Chief Operating Officer BioStorage Technologies, Inc. Tel. +1 866 697 2675 +49 6155 898 1011 www.biostorage.com 40 The specifics of a sample management strategy may vary, depending on the nature and intended use of the biospecimen, as well as the size and complexity of the collection. To ensure biospecimens are properly handled, transported and stored, companies should be aware of and follow Good Storage Practices (GSPs) guidelines. While GSP is not a regulatory mandated requirement, specific good storage practice guidelines have been established by the International Society of Biological and Environmental Repositories (ISBER) and governmental organizations like the US National Cancer Institute (NCI). In 2008, ISBER drafted guidance of best practices for the collection, storage, retrieval and distribution of biological materials for research (Table I). Industry experts expect these guidelines to evolve into regulations such as those that exist in other GxP environments (for example, GTP, GCP, GLP, and GMP). Today, the guiding principles of GSP mandates the standardization of sample handling and management processes to ensure samples are prepared and stored in consistent conditions.5 Because it may take years before specimen samples are needed for future research, testing, or audits, samples must be stored in highly specialized and consistent conditions, often for decades. To maintain sample integrity for such long periods of time, standardized, secure and compliant storage is crucial. A sample that has maintained the appropriate storage temperature will yield better results than a sample that has undergone fluctuations in temperature because of poor handling or storage practices.6 In addition, proof of sample conditions, temperature history and chain of custody must be proven if samples are to be viable for inclusion. Examples of the various components of GSP include • Secure facilities and robust quality assurance measures to ensure specimens are stored in compliant conditions at all times. • Qualified staff that has been trained and certified in global sample transportation procedures, including regulatory and customs issues. • Temperature monitoring and recording of samples around the clock with a comprehensive, uneditable audit trail and automatic notification system. www.pharma-mag.com • Business continuity plans, back‑up power and redundant systems to protect sample integrity during emergencies. Information Systems for Specimen Management Although proper storage and transportation are critical, specimens are useless unless they can be located with their associated data, in a timely fashion. In the past, researchers applied ad hoc tracking systems, such as spreadsheets, to track and plot information associated with biospecimens. Today, the complexity of clinical trial research has rendered these outdated and archaic systems inefficient to handle expanding biospecimen inventories. The ideal system should offer tracking and reporting processes through all stages of a sample’s shipping, handling and storage life cycle. Often, critical information about a sample is “missing” or “inaccurate,” which can lead to costly study‑specific errors. To this end, a solid informatics approach includes integration of sample preregistration, cataloging of qualitative and quantitative information at the time of accessioning, as well as defined SOPs regarding sample discrepancies. Because pharmaceutical and biotech labs typically implement a wide range of information systems, specimen management systems should seamlessly interface with other systems, provide global data integration and access and be highly configurable to easily integrate with a variety of laboratory workflow models. Recent innovations have even expanded information management systems to include mobile and web‑based solutions. The integration of sample storage, consent authorization and clinical result data is another area of expansion occurring as a result of the advent of new technology systems. Connecting information on sample storage location, temperature and pretesting evaluation with the resulting data from a clinical study can enable researchers to improve their selection of samples for biomarker testing and shorten personalized medicine research timelines. Conclusion Whether samples are outsourced and stored offsite at a global biorepository or managed onsite by an insourced service provider, a robust infrastructure for biospecimen tracking and distribution will be required to support a successful comprehensive sample management strategy. This combination of GSP and innovative technology streamlines the process of sample management; ensuring samples and information are readily available for today and tomorrow’s research initiatives. Now is the time for organizations to establish a comprehensive management strategy that incorporates and dictates how samples are handled, stored, transported and documented throughout their entire life cycle. September/October 2011