Abstract
The genomics, proteomics, clinical, and drug discovery laboratories have a growing need to maintain valuable samples at ultra-low (−80°C) temperatures in a validated, secure environment. Automated sample processing systems have until now required manual (off-line) storage of samples at −80°C, reducing system reliability and speed. Both of these important needs are addressed by the Sample Process Management System being introduced by BIOPHILE Inc. Conventional sample management processes, such as storage, retrieval, and cataloging, are increasingly strained by the growing sample populations. There are variable sample types, access requirements and storage requirements. Security and inventory procedures are implemented manually. The evolving technologies present in the laboratory cannot interface with conventional manual storage techniques. Addressing these limitations, the primary benefits of BIOPHILE's solutions are:
Fully validated sample management process that coordinates the life-cycles of samples and their related data. Robotic technology to securely store and retrieve samples, improving their accessibility and stability. Thermal shock is reduced, improving sample longevity and quality. The robotic technology allows integration with larger automation systems. A process program to develop a Sample Management Strategy. This strategy is developed by analyzing long-term research goals, current baseline processes, and identification of current sample life cycles. A full validation documentation package can be generated, providing a high level of quality assurance. Improved sample visibility and quality assurance — auto mated sample population cataloging; controlled sample management access and security.
INTRODUCTION
Traditional approaches to storing and tracking frozen samples in the laboratory are error-prone, time consuming, and incompatible with automation systems. Even more importantly, they do not allow for validated processes to be built around the sample management phase. Labs involved in genomics, drug discovery, screening, repositories, and cell biology place samples into storage at −80°C. Typically, these samples may consist of purified DNA or RNA, cells, enzymes, tissue, and other compounds, oligos, primers, and probes. Samples are traditionally placed in ultra-low temperature (ULT) −80°C freezers within racks that may contain varying sample types; the racks may contain samples belonging to different groups or studies. These racks often accumulate large masses of ice and frost that may restrict access to samples. This ice buildup necessitates the occasional defrosting of the freezer, a process that places the samples at risk of loss or damage. Very little access control and tracking is enforced. With the increasing number of samples being processed in today's labs, combined with the high value of these samples, a validated approach adapted from Good Manufacturing Practices is needed.
BIOPHILE Inc., has introduced a unique Sample Process Management system to the ULT market. This system provides the lab with a validated sample process, allowing secure access control to samples, complete sample histories, and automated storage and retrieval. This paper introduces the BIOPHILE PROCESS™ the ultra-low temperature automation technology, and the information technology.
OVERVIEW OF THE BIOPHILE SAMPLE PROCESS MANAGEMENT SYSTEM
At the core of BIOPHILE's philosophy is the concept of validation. The FDA defines validation as, “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”1
Internally, a Good automation Manufacturing Practices (GaMP) approach is used to derive a structured validation plan for each manufactured system. A finely detailed User Requirement Specification (URS) has been formulated based upon the customer's critical to quality parameters. The URS focuses on the application of the technology within the customer's research environment. The URS provides the foundation for the Process Qualification (PQ), the final challenge in the validation process. From the URS, a Functional Specification has been created detailing the standard operating parameters of the technology. This document includes hardware and software design specifications and testing procedures. The Functional Specification provides the foundation for the Operational Qualification (OQ). Finally, a Manufacturing Specification has been created, detailing the actual manufacturing processes necessary to create and test the technology prior to release. This provides for the first step of the qualification process, Installation Qualification (IQ.
The BIOPHILE PROCESS™ is an eight-step program designed to validate the emerging processes enabled through the application of the technology. It concurrently develops a Sample Management Strategy for the customer by examining long-term objectives and current environments, resulting in a process driven and validated solution to the customers sample management needs.
Validated sample management processes are crucial to those laboratories performing clinical trials, screening, DNA matching, or working with irreplaceable samples.
AUTOMATION TECHNOLOGY
BIOPHILE's Sample Process Management System centers on a unique robotic technology that operates in a −80°C ULT environment. The robotics are designed to automatically store and retrieve up to 931 bar-coded microtiter plates (or other containers with a similar footprint). Deep-well plates can also be accommodated, with some reduction in capacity. The allotment of storage space for standard and deep-well microtiter plates is user-selectable. BIOPHILE will also supply freezer boxes compatible with the system, which may be used to store cryovials, tissue samples, or other storage vessels. The key benefits of the BIOPHILE automation technology are:
AUTOMATED STORAGE AND RETRIEVAL OF ∼1,000 MICROPLATES AT −80°C
The BIOPHILE automation consists of a specially tuned 6-axis robot that operates at −80°C. The robotics guide the storage container from the exterior, through the barcode reading and dehumidification process, and into the freezer interior. There, the container is transported into its storage location. The system also functions at room temperature, which is useful during system Installation Qualification. Sample access is performed within 30 seconds. At each phase of the storage process, error checking is performed. In any event that might compromise the integrity of the sample, the system alerts the operator and stops to await further actions. All error recovery and disaster recovery procedures are fully documented.
BIOPHILE Interior
BIOPHILE Exterior
AUTOMATED FROST ELIMINATION
Another benefit of the BIOPHILE system is the lack of frost buildup in the freezer compartment. Frost occupies valuable freezer space, makes access to samples difficult, and requires periodic removal. Defrosting a laboratory freezer places samples at risk, due to the need to move the samples into another location. The BIOPHILE system maintains a constant temperature in the freezer. It eliminates frost buildup by:
Dehumidifying the container and the volume of air surrounding it before placing the container inside the freezer. This is accomplished by the use of an airlock that containers pass through on the way into the freezer chamber. A small volume of dry nitrogen is used to flush the humid warm air from the chamber before the container is stored. The rate of utilization of nitrogen is very low; a full tank of gas lasts 3–6 months during heavy use.
Reducing the size of the portal opening. Rather than opening a typical freezer door, causing a large displacement of cold dry air with humid room air, the BIOPHILE system uses a very small, automatically controlled doorway. This door allows very little interchange of air.
Reducing the time the freezer door is opened. The handoff of the container from outside to inside is performed in less than 10 seconds, which is much quicker than a typical manual operation.
The airlock has been designed to allow access to containers by microplate grippers common to contemporary laboratory automation equipment.
INFORMATION TECHNOLOGY
As much focus has been placed on the development of BIOPHILE's information technology as on its automation. An easy-to-use touchscreen interface provides the most obvious point of contact between the laboratory manager or technician and the BIOPHILE system. The touchscreen interface is located on the front panel of the unit, directly above the airlock portal. For systems integrators, a rear-mount option is available. The touchscreen provides all sample access functions for the lab technician, as well as user/group account controls for the administrator. Access control is provided by unique user ID's and passwords. Other user identification systems are possible, such as fingerprint recognition or radio frequency identification (RFID).
The information technology allows the lab technician to catalog samples, view sample access histories, check for sample access frequency and expiration, and generate graphs on sample temperature and possession time. These tools improve sample visibility and quality assurance. Automated sample population cataloging is also supported.
Remote control of the system is supported through a RS232 serial interface. This interface allows secure, controlled access of samples by other automation systems. An Ethernet interface is also provided.
FREEZER TECHNOLOGY
The freezer enclosure and mechanical components are based on Harris ULT technology. A Harris cascade freezer system comprised of two, 1.5 horsepower, semi-hermetic compressors provides the basis for the mechanical system. The freezer component has been OEM configured by Harris to support the additional robotics equipment and to meet BIOPHILE's specific requirements. One such requirement is the serviceability of the freezer components and the robotic components. Service and maintenance of the robotics can be performed independently of the freezer operation. All electronics, motors, and sensors can be replaced without compromising the security of the samples within the freezer. The Harris platform provides proven quality and reliability, and backup coolant and remote alarms are provided for additional security.
CORPORATION BACKGROUND
Research at the Medical Automation Research Center at the University of Virginia, funded by the Carilion Biomedical Institute of Roanoke, Virginia, was the basis for developing an automated storage and retrieval system at −80°C. BIOPHILE, Inc., was created to develop, manufacture and market this automated ULT as an integral part of a unique sample management system, known as the BIOPHILE PROCESS ™.
CONCLUSION
BIOPHILE has introduced a new enabling technology to provide the laboratory with a validated, automated approach to storing samples in a ULT environment. This approach consists of a validation process occurring before, during, and after installation of the BIOPHILE automated ULT system. BIOPHILE's ULT technology consists of a unique information technology platform, sophisticated robotics designed to operate reliably at −80°C, and an OEM-configured Harris ULT freezer. The system is suitable for any lab working with valuable samples, or those labs requiring compatibility with other information systems and automation systems.
Technology features at a glance
Footnotes
1
FDA Guidelines on General Principles of Process Validation, May, 1987.