IMPROVING PRODUCTIVITY AND COMPLIANCE IN THE BIOANALYTICAL LABORATORY

IMPROVING PRODUCTIVITY AND COMPLIANCE IN THE BIOANALYTICAL LABORATORY The Waters Regulated Bioanalysis System Solution featuring the UNIFI Scientific ...
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IMPROVING PRODUCTIVITY AND COMPLIANCE IN THE BIOANALYTICAL LABORATORY The Waters Regulated Bioanalysis System Solution featuring the UNIFI Scientific Information System The bioanalytical laboratory is facing some of the greatest challenges in the pharmaceutical industry. Increasing demands for more sensitive assays as well as faster turnaround of study information can seem at odds with the need to meet the complex and rigorous regulatory guidelines, such as assay validation, incurred sample reanalysis (ISR), metabolites in safety testing (MIST), and compliance. At the core of the bioanalytical challenge is the need to acquire, process, and report data in a 21 CFR Part 11 compliant environment. This requires an analytical system that meets performance demands, fits in with laboratory workflow and practices, is flexible enough to evolve as technology advances – yet is still compliant and secure. To date, the bioanalyst has addressed these problems by building their own system comprised of the best available components from different manufacturers. While this may have delivered the required level of assay sensitivity and performance, it has resulted in significant workflow, troubleshooting, system qualification, and software validation challenges. This compromise-based approach makes it difficult to manage change control and lacks flexibility to evolve and adopt new technology. ■■

This white paper demonstrates how the Waters Regulated Bioanalysis System Solution, built upon the UNIFI Scientific Information System, meets the converging needs of investigators, analysts, managers, and QA and IT professionals by uniting best-in-class sample preparation, UPLC/MS technology, software, and support services in a single platform purpose-built for quantitative bioanalysis.

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It illustrates how the platform integrates into the workflow of the bioanalytical laboratory in a secure and compliant manner, and enables better decision making within the drug development lifecycle of a pharmaceutical organization and its respective partners.

int roduc t ion Multiple challenges and imperatives ahead for the bioanalytical laboratory The regulated bioanalysis laboratory is charged with rapidly developing methodologies to support the pre-clinical and clinical development of a candidate pharmaceutical. The goals of these laboratories are to increase sample throughput and assay sensitivity to drive products to market faster. At the same time, such laboratories are being asked to do more with fewer resources and often fewer staff or less-trained staff. Until recently, the regulated bioanalytical laboratory has focused on generating concentration data on the target analyte or analytes. As the regulatory requirements change, there is now a need to provide an increasing amount of quantitative and qualitative data on metabolites and biomarkers in the samples. With this pressure to provide high-quality data in a short time frame, each part of the bioanalytical process must become more efficient and more integrated. All of these processes must be carried out in a GLP/GMP, 21 CFR Part 11 compliant manner, hence these laboratories require hardware and software tools that help them meet these regulatory challenges without compromising the productivity or flexibility of the laboratory. New regulatory guidelines for ISR, MIST, and matrix factor place an extra level of complexity on the bioanalytical laboratory. These new guidelines require bioanalytical methods to be developed with increased robustness, reliability, and specificity. This in turn demands a higher level of performance from all components of the analytical system. The sample preparation approach must reliably remove proteins and lipids such that samples can be reproducibly analyzed with a high level of confidence. The chromatography system, which plays a critical role in the bioanalysis methodology, must resolve the analyte of interest not only from the endogenous components in the sample but also the drug-derived metabolites. The mass spectrometer provides further specificity to detect target analytes with the required sensitivity.

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While there is an increased emphasis being placed on drug metabolites, there is also more regulatory interest in matrix effects, with requirements being cited on calculation of matrixderived analyte suppression and ISR; both of these subject areas require improved sample preparation and data analysis and interpretation. In tandem with these escalating regulatory challenges, the need for assay sensitivity has not diminished. Peptide and protein therapeutics (biologics) as well as low-systemic-exposure inhaled pharmaceuticals are driving needs for highly specific, robust, high-sensitivity assays in the picogram-per-milliliter (pg/mL) range. These analytical challenges require a new generation of instrumentation that can meet these detection challenges as well as improve the method development process and detect putative drug metabolites. Meanwhile, the future of DMPK studies is evolving rapidly itself: dried blood and sample spots (DBS) as well as micro dosing and sampling all will require new analytical solutions that must be integrated into existing workflows and platforms.

A solution ready for bioanalysis’ next generation To address these challenges of performance, flexibility, compliance, and productivity, Waters has created a new generation of system solutions. The Regulated Bioanalysis System Solution is an application-focused platform that enables the bioanalyst to combine improved workflow-driven analysis, data acquisition, and reporting with best-in-class sample preparation, tandem quadrupole mass spectrometry, and UltraPerformance LC® (UPLC®). All this is achieved with the next generation of compliant-ready software for GLP/GMP data acquisition and management. This platform’s intrinsic design facilitates data standardization so that information may be exchanged and shared among departments and third-party partners globally. It enables all laboratory functions to work with a common backbone of analytical information comprised of successful methods, processed results, and historical data and reports.

The Regulated Bioanalysis System Solution

Purposeful technology integration

The world’s first integrated and compliant-ready platform for regulated bioanalysis laboratories amplifies the benefits of Waters’ market-leading analytical technologies:

The Waters Regulated Bioanalysis System Solution combines the throughput and resolution attributes of Waters’ award-winning UPLC columns and instrumentation with industry-standard sample preparation and groundbreaking MS technologies. These technologies have all been purposefully designed to work together in a complementary manner to achieve maximum analytical performance.

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Oasis ® and Ostro™ sample preparation (SPE) solutions and ACQUITY UPLC Column technologies allow the bioanalytical scientist to quickly and easily develop robust and reliable methods that can be easily transferred globally.

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ACQUITY UPLC® I-Class System, featuring the lowest system volume, minimized band spreading, and ultra-low autosampler carryover, delivers the highest chromatographic performance with the broadest accessible analysis range and reduced analysis times.

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Xevo TQ-S Mass Spectrometer, featuring our ground breaking StepWave™ off-axis ion source technology for unprecedented levels of sensitivity and accuracy, delivers the ultimate sensitivity and robustness for bioanalytical assays.

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UNIFI™ Scientific Information System, an interactive workflowdriven data platform for flexible instrument control, advanced data processing and mining, and comprehensive reporting, with compliant-ready GLP/GMP laboratory compatibility that enables routine deployment throughout your organization.

The Oasis µElution plate generates high-concentration samples in just a few microliters of elution solvent, allowing the direct injection of the sample onto the chromatography system and eliminating the need for drydown. UPLC Technology then exploits the performance of sub-2-µm hybrid particle technology to derive high-resolution chromatograms while minimizing analytical run times. This enables faster, more robust, and reproducible methods with reduced interferences and lower LOQs. These narrow peaks produced by UPLC pose a significant challenge to detection by mass spectrometry, requiring high data capture rates to collect a sufficient number of data points across a peak for accurate quantitation. The Xevo TQ-S has been specifically designed to deliver the highest level of assay sensitivity at the fastest of acquisition rates. We have united these individual components into the most capable, compliant-ready, workflow-driven solution for the bioanalytical laboratory. Workflows built into UNIFI specifically for the bioanalyst include:

Waters has holistically integrated our SPE, UPLC, MS, and informatics technologies into a single compliant-ready system solution to ensure that your laboratory is on the smart path to addressing the diverse challenges of bioanalysis.

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· Protocols for SPE method development

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· Parameter promotion for LC/MS method development

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· Automated MRM development for small and large molecules

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· Predict and generate MRM methods to monitor biotransformations at multiple sites with iMRM

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· Matrix effects measurement and reporting

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· ISR templates

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· Secure data transfer with LIMS

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· Automated system qualification

Whether you are developing methods, analyzing pre-clinical or clinical batches in a regulated laboratory, managing a laboratory, or you are responsible for this overall process, the Waters Regulated Bioanalysis System Solution delivers unprecedented levels of productivity, performance, and compliance. 3

From its Welcome page, UNIFI provides quick access to the tasks you need to accomplish.

Bioanalytical method development The method development process in bioanalysis can be divided into three discrete but interlinked phases: sample preparation, chromatography separation, and mass spectrometry detection. To aid in all three, we have developed a unique series of technologies and structured approaches that deliver a logical workflow for bioanalytical method development. To simplify the approach to MS methods development, the Xevo TQ-S has been designed with Waters’ philosophy of Engineered Simplicity™, combining the highest performance in mass spectrometry with system versatility and simplicity of operation. The Xevo TQ-S is equipped with IntelliStart™ and on-board fluidics that enable an inexperienced scientist to develop reliable methods. The system automatically infuses the compound solution, optimizes the mode of ionization (APCI or ESI), selects the most intense precursor ion and product ion(s), then will maximize response by optimizing the collision energy and cone voltage settings – and all this can be achieved in just a few minutes. This process is completely automated in the UNIFI Scientific Information System utilizing the compound library. Additionally, samples can be managed and methodologies can be stored for future use. The development of the chromatographic and sample preparation methodology requires monitoring of both the analyte molecule and the background signal to optimize sample response and sample throughput. The Xevo TQ-S is equipped with novel RADAR™ Technology, an information-rich acquisition approach that allows the simultaneous collection of multiple reaction monitoring (MRM) and full scan data to simplify method selection and optimization. The process of developing an SPE method can be complex; however with the Oasis family of solid phase materials, we have developed a simple 2x4 approach that allows the best method to be selected quickly with the minimum number of experiments.

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This rapid SPE approach is ideally paired with the chromatographic performance of the ACQUITY UPLC I-Class System. The ultra-low dispersion of the system and its fast, flow-through needle autosampler delivers the highest resolution chromatography with rapid throughput. ACQUITY UPLC BEH Columns enable scientists to evaluate both high and low pH separations, to maximize selectivity and sensitivity. Tying together the processes of developing a bioanalytical method, UNIFI software also includes secure, customizable templates and processing algorithms. Analysis templates allow users to easily create new samples lists and view and approve batch results in a predefined way, including the application of electronic approvals by managers as required. The purposefully designed processing algorithms enable rapid, reliable, and secure data processing, containing required audit trails, allowing both analysts and managers to achieve the final required results in a single application. With these capabilities, the Waters Regulated Bioanalysis System Solution allows complex tasks such as matrix factor calculations and batch release reports to be carried out quickly in a secure manner. These solutions combine to deliver a fast, simple, powerful solution for method development.

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Determining matrix factor The matrix effect calculator is an example of a completely automated end-to-end workflow solution available with this unique platform. The sample set is defined in the acquisition template, then the ACQUITY UPLC I-Class and Xevo TQ-S systems automatically inject sample blank and solvent blank as well as authentic standards. The analyte is automatically infused post-column, via integrated sample fluidics on the Xevo TQ-S. The UPLC/MS data is then automatically processed within the UNIFI software to calculate the matrix suppression and matrix factor. A report is automatically generated and can be reviewed and electronically approved. Matrix effect calculator sample list.

UNIFI shows results warning for a 2-minute gradient where percent suppression limits for the matrix factor are being approached.

In a view of the raw and processed data, the component in matrix suppression is shown.

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Validation, qualification, and compliance Operating within regulations is the key to success in a bioanalytical laboratory. Data must be acquired in a secure and compliant manner using software that has been validated and meets GLP/GMPs and Part 11 regulations. This can often take a significant amount of time and effort to complete. The UNIFI Scientific Information System for informatics and data management is intrinsically designed to meet these regulations, enabling bioanalytical labs to quickly install and validate the system. UNIFI’s underlying data security is built in to its extensible, multi-tiered design: the system’s advanced UPLC/MS workgroup is hosted in a service-based architecture that maintains productivity and data integrity. UNIFI’s Qualification Center facilitates confident and rapid system installation and validation. As UNIFI software is developed under a Quality Software Development Lifecycle, Waters has documented evidence of the large amount of testing performed during product release. This documentation is available to users or potential users during an on-site audit. We can also provide summary information about our development processes as part of a postal supplier assessment. This type of documentation can be used during risk assessment to considerably reduce the validation testing required by the laboratory, as outlined in GAMP 5 recommendations. For laboratories that require assistance in their validation effort, Waters can also offer Extended Qualification procedures which include testing the security, audit trails and e-record/signature capabilities. Further detailed help can also be offered through Core or Extended Computer System Validation services, scaled to the needs of the individual laboratory.

The Qualification Center within UNIFI.

Qualification and validation activities are streamlined by being managed within a single software platform.

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Complete platform security, from audit trails to granular access controls Bioanalytical data systems in regulated laboratories must contain a full audit trail of all methods, parameters, manual changes, and user actions – essential for audits and inspections. It must also contain defined roles and privileges for each user such that critical actions can be controlled. The UNIFI Scientific Information System is built on a new secure data platform that provides granularlevel control of system access with user roles and privileges that are managed by the administrator though a single administrator application for the entire lab. This allows an auditor be confident that the software is managed in a controlled way. Finally, UNIFI software employs secure acquisition via a dedicated device with buffering capabilities, and stores the data files and results files in a secure database for simple search and retrievability. These security features not only support system use and management to address regulatory requirements for bioanalytical laboratories, they also extend to the transfer of sample lists and data to and from a LIMS system.

Secure LIMS data transfer Many bioanalytical laboratories employ LIMS systems to manage and track samples and results. In order to maintain the secure nature of the data, the sample run list and data need to be transferred to and from the LIMS system and the LC/MS data system in a secure manner. UNIFI software utilizes a secure and seamless data transfer protocol to transfer sample sequences and runs to and from a LIMS system, such as Watson LIMS, thus allowing fast and easy sample list creation and data management. To complement data acquisition, the data review and approval process is similarly streamlined within UNIFI. When users are set up with distinct roles and functions, the approval of a batch of samples follows a simple, customizable hierarchy that defines a distinct set of privileges for each user. UNIFI provides the flexibility to use both regulated and non-regulated roles, with access levels that can be matched to the analytical purpose. For example, a user can log off and system will continue an acquisition, while other users can queue batches, enhancing laboratory productivity as well as maintaining security. UNIFI also enables electronic signatures to allow fast and secure batch review and approval. Once batch results have been approved, peak areas and related results can be seamlessly exported back to a LIMS system for further processing.

Data import from Watson LIMS.

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After import from LIMS and analysis, reviewing response ratios across QC samples.

Electronically signing an approval of the LIMS batch report.

Selecting the final data for export from UNIFI to LIMS.

Pushing the results to LIMS.

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Reporting Collating and formatting the data generated for individual batches, overall studies, and validation runs can be a time-consuming and tedious process. The batch reports often require that standards, QCs, and sample data to be separated into different tables for reporting. UNIFI software streamlines reporting of such data with its customizable report template. Within these report templates it is possible to display the statistics such as coefficients of variance and residuals for standards and QCs, which have been defined and calculated in the analysis, and to indicate graphically if these fell within the predefined or automatically calculated acceptance limits. The templates can be configured to automatically compile data on standards and QCs from several batches, providing overview of an entire study set. The reporting can be controlled and monitored using an easily-accessible audit trail and approved with an e-signature process.

A method developer, whose access controls are limited within UNIFI, sends a signed report for approval.

The lab administrator receives a notification that the report is available to review.

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Approval of the report is recorded with an e-signature and comment, including time and date stamp among other metadata that makes it easy to search and retrieve as necessary during an audit.

CONC L U S ION The modern bioanalytical laboratory faces numerous challenges: improving assay sensitivity, fast-tracking method development, increasing throughput, streamlining secure data transfer to-andfrom LIMS, and simplifying data reporting. All of this must be accomplished in a secure and easy-to-use analytical environment. The Waters Regulated Bioanalysis System Solution brings together best-in-class sample preparation, liquid chromatography, and tandem quadrupole mass spectrometry with a novel user focused, state-of-the-art scientific information management system that delivers a entirely new level of performance and security. As the world of bioanalysis and DMPK continues to evolve, bioanalytical laboratories will face new challenges such as micro sampling, dried sample spot analysis, and large molecule bioanalysis. The new UNIFI-based bioanalytical platform from Waters is built with these enhancements.

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Its architecture and unique Qualification Center enables a fast and structured approach to system qualification, which allows updated, upgraded, or new software and hardware technologies to be added and re-qualified with minimal disruption.

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Within this secure environment, calculations such as matrix effect, assay validation, and batch study summaries can be produced, following a simple, automated workflow-driven process. This enables you to meet the compliance standards set forth by your organization and the productivity demands for your laboratory.

The Waters Regulated Bioanalysis System Solution, featuring Oasis and Ostro SPE, ACQUITY UPLC I-Class, Xevo TQ-S, and the novel UNIFI Scientific Information System, delivers the ultimate system performance for bioanalytical laboratories today, and prepares your laboratory to evolve in step with the next frontier in bioanalytical sciences.

Waters, ACQUITY UPLC, UltraPerformance LC, UPLC, Oasis, and Xevo are registered trademarks of Waters Corporation. UNIFI, Ostro, Engineered Simplicity, IntelliStart, RADAR, and T he Science of W hat’s Possible are trademarks of Waters Corporation. All other trademarks are the property of their respective owners. ©2011 Waters Corporation. Produced in the U.S.A. June 2011  720003933EN AO-PDF

Waters Corporation 34 Maple Street Milford, MA 01757 U.S.A. T: 1 508 478 2000 F: 1 508 872 1990 www.waters.com

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