Abstract
Pharmaceutical research and development has entered a new era, shifting from the one-size-fits-all approach of traditional medicine to patient-specific therapeutics. This change in treatment methodologies has placed an increased emphasis on well-preserved, well-documented biospecimens. Due to these advancements in medicine, specimen handling processes need to be in accordance with current Good Practice (GXP) quality guidelines and regulations, including Good Manufacturing Practices (GMPs), Good Laboratory Practices (GLPs), and Good Clinical Practices (GCPs), to ensure the safety of valuable biospecimen samples and their associated data.
GXP guidelines delineate most aspects of clinical research. This is especially true for chain-of-custody documentation, as it provides a traceable record that guarantees unbroken control over a document, raw data, or a sample and its containers from initial collection to final disposition.
Although establishing chain-of-custody can be a demanding practice, the process of verifying who has possession of specimens can be streamlined if an organization outlines chain-of-custody guidelines in their Standard Operating Procedures (SOPs). These processes and procedures ensure uniform application of best practices and successful knowledge transfer. As such, this article will outline the necessary components of establishing a highly visible and compliant chain-of-custody, including: maintaining 21 CFR Part 11 compliance; installing validated, redundant equipment for specimen storage and transportation; employing temperature-monitoring and -tracking devices; and best practices for implementing inventory and data management systems as well as audit trails.
Introduction
The availability of high-quality biospecimens allows researchers to conduct a wide range of analyses that not only allow for a better understanding of the genetic and molecular changes involved in the progression of diseases, but can also be used for assessing the effectiveness of novel drugs and therapeutics in a particular patient population. For this reason, specimen handling processes should be in accordance with current Good Practice (GXP) quality guidelines and regulations, including Good Manufacturing Practices (GMPs), Good Laboratory Practices (GLPs), and Good Clinical Practices (GCPs), to ensure the safety of valuable biospecimen samples and their associated data. GXP guidelines delineate most aspects of clinical research and have a particular focus on the maintenance of detailed records. This is especially true for chain-of-custody documentation, as it provides a traceable record that guarantees unbroken control over a document, raw data, or a sample and its containers from initial collection to final disposition. 1
Although establishing chain-of-custody can be a demanding practice, the process of verifying who has possession of specimens can be streamlined if an organization outlines chain-of-custody guidelines in their Standard Operating Procedures (SOPs). These processes and procedures ensure uniform application of best practices and successful knowledge transfer. SOPs should be incorporated into routine training programs and be regularly updated to guarantee compliance to an expanding array of regulatory requirements from a number of entities. As such, this article will outline the necessary components of a highly visible and compliant chain-of-custody, including:
Maintaining 21 CFR Part 11 Compliance Installing validated, redundant equipment for specimen storage and transportation Employing temperature-monitoring and -tracking devices Best practices for implementing inventory and data management systems as well as audit trails.
Maintaining 21 CFR Part 11 Compliance
The Code of Federal Regulations (CFR) Part 11 was implemented in 1997 to allow the US Food and Drug Administration (FDA) to accept electronic records and signatures in place of paper records and signatures as compliant. The regulation outlines controls for ensuring that electronic records and signatures are trustworthy, reliable, and compatible with FDA procedures and as verifiable and traceable as their article counterparts.
21 CFR Part 11 also specifies a number of requirements for software systems to enable trustworthy and reliable electronic records and signatures. These software requirements must be met for the resulting electronic records to comply with FDA's guidelines. If an organization does employ electronic records and signatures, but fails to comply with these system requirements, the FDA can cite the firm for violating the underlying regulation. For example, if a drug company maintains written complaint records in electronic form, but the FDA finds that these records are unacceptable substitutes for article records, the FDA would charge the firm with violating 21 CFR 211.198(b). The potential impact might include FDA-requested recall, FDA-mandated recall, warning letter, seizure, injunction, prosecution, civil penalties, or detention. 2
Validated Equipment for Specimen Storage
The FDA's GXP guidelines require all systems that govern any GXP process—including GMPs, GLPs, and GCPs—be validated. 3 Validation processes ensure that systems meet their intended needs and satisfy regulatory requirements. For chain-of-custody, this typically includes validation of tracking systems, temperature-monitoring devices, specimen-management software, and storage equipment. As an example, freezers and refrigerators used to store biospecimens require documented thermal mapping. As a critical element of validating compliance, these measures ensure that specimens are being stored in optimal conditions with the correct temperature requirements. Refrigerators and freezers should also be calibrated annually with National Institute of Standards and Technology (NIST) traceable probes to ensure temperature equipment is operating in the acceptable, predetermined temperature range. 4
To ensure the safety and efficacy of potential drug candidates as well as drugs already on the market, the FDA needs to be able identify the history of biospecimens and data generated from the clinical studies. The FDA recommends that biological samples generated during clinical trials be maintained through a regulatory filing process and can even request further analysis of drugs already on the market. Consequently, all biospecimens generated during clinical trials should remain stored in compliant conditions throughout the life cycle of the drug and be easily retrieved within hours, if necessary.
Validated Containers for Specimen Transportation
At various phases in drug development, biospecimens are transported between collection sites, analytical labs, and biobanking facilities that are often spread out over several geographical areas. As a result, cold chain management has developed into a critical element of pharmaceutical development. Cold chain management defines how temperature-sensitive products and biomaterials, such as clinical trial specimens, active pharmaceutical ingredients, and microbiological and viral samples are packaged, transported, and stored throughout the research and development process. Weakness at any point in the chain can compromise specimen or product integrity, breach security, delay shipments, and ultimately have a negative impact on chain-of-custody.
Validated packaging materials and effective packing techniques, including insulation, temperature-tracking devices, and some form of refrigerant, provide additional insurance throughout the cold chain. Shipping cartons must comply with International Air Transport Association (IATA) and US Department of Transportation (US DOT) guidelines.5,6 Validation processes should be described in an organization's SOPs to ensure that methods are widely recognized and constantly met by personnel. Validated shipping cartons may be purchased, but some organizations choose to perform validation using internal resources or hire a third-party organization to perform and help with portions of the validation.
Specimen Tracking and Monitoring
While in transit, organizations can use temperature-monitoring devices to ensure the integrity of their shipments. Temperature monitors are used to track the temperature of materials being shipped. If temperature excursions outside the previously determined temperature range occur, it could compromise the integrity of biospecimens; therefore, logistics personnel should evaluate any deviation. As a SOP, corrective action should be implemented where necessary and documented. This allows for a full historical account of specimens, which is a valuable component of transparent chain-of-custody.
Specimen tracking is also critical for establishing a transparent chain-of-custody as it allows researchers to keep an around-the-clock status of their specimens. The ideal system should eliminate article-based tracking and report processes through all stages of a specimen's shipping, handling, and storage life cycle. Therefore, organizations should employ a system that tracks clinical data throughout workflow while managing temporary or transit storage locations with intricate chain-of-custody functionality. This will streamline processes and ensure that valuable samples are easily located and retrieved, as needed.
Data Management and Audit Trails
Audit trails are required by various regulatory agencies to help establish that specimens have not been compromised while in transit or in storage. For a comprehensive audit trail, records should form a complete history of the specimens' life cycle and include:
The type of specimen, such as tissue, blood, or plasma The donor and location where the specimen was collected Date the specimen was obtained Storage and shipping conditions of the specimen at all times The final destination of the specimen.
In addition to audit trails, information management plays a critical role in drug development. Researchers are analyzing a vast amount of clinical information about patients' health and disease from patient records and clinical trials. These data help researchers identify patterns and disease subtypes, therefore leading to effective strategies for diagnosing and treating disease in new and efficient ways.
Conclusion
The demands for regulatory compliance, documentation, audit trails, and specimen integrity make validated chain-of-custody procedures a necessity to protect and ensure the value of clinical data for present studies as well as for future studies and analyses. However, for clinical data to be meaningful and accurate, organizations should be capable of reporting chain-of-custody processes through all stages of a specimen's life cycle. Personnel should follow these processes whenever samples and data are collected, transferred, stored, analyzed, or destroyed. This is especially important today, as the recent focus on molecular therapies, personalized medicine, and biomarker discoveries in medical research have placed an increased emphasis on quality biospecimen samples.