Implementing Electronic Signature Requirements in an existing LC-MS/MS Data Processing & Reporting System

Robert A. Bethem, John W. Cornacchia, Scott Serl, Shelly Weagraff and Jo Marie Smolec
Alta Analytical Laboratory

Ike D. Tabani
Innovative Automation

Presented at the 47th ASMS Conference on Mass Spectrometry and Allied Topics,
June 13 - 17, 1999,  Dallas, TX.

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Contract research organizations (CRO) operating under FDA-GLP are faced with two opposing challenges; maintaining high productivity and compliance with the evolving regulatory electronic record-keeping requirements. Over the past ten years, LCMS laboratory managers have steadily improved laboratory productivity via automation of data acquisition and reporting. The drive towards laboratory automation and compliance with electronic record keeping is converging to define a common platform necessary to achieve the paperless CRO. FDA has recently presented guidance regarding electronic record keeping requirements issued in Part 11; Electronic Records; Electronic Signatures (21 CFR 11)^1,2 . The purpose of Part 11 was to address the electronic record keeping and signature requirements in "Paperless Record Systems". Some of the key requirements for regulated systems include: - Validation - Ability to Generate Accurate and Complete Copies - Archival Protection of Records - Audit Trails - System Controls - Personnel Training and Qualifications ALTA has incorporated the electronic record keeping and signature procedures into ALIS98™, an LCMS report writer^3-5 that are required of regulated systems. The purpose of this presentation is to describe our approach to implementing these new features including an electronic audit trail, encrypted electronic signatures and enhanced system controls towards satisfying the FDA requirements. Much of the design considerations were based on information presented at the 1998 SQA Workshop (Alexandria, VA) as well as presentations available at the FDA web site (http://www.fda.gov). We invite discussions with others who supply FDA with equivalent data as to how they accomplish the same goal.

References 1. Electronic Records; Electronic Signatures; Final Rule (21 CFR Part 11). 2. The FDA Inspection Program. J. McCormack (FDA). Presented at the SQA Workshop Advanced QA Techniques, July 10, 1998. Alexandria, VA. 3. ALIS98 Users Manual. Innovative Automation. 1998. 4. Evaluation of the Effect of Regression Model Selection on Quantitative LC-MS/MS Data. Robert A. Bethem, John W. Cornacchia, Elaine K. Fukuda, Alen Chan and Ike D. Tabani. Presented at the 45th ASMS Conference on Mass Spectrometry and Allied Topics, 1997. 5. ALIS-DMA/DMPRA: A New LC/MS Pharmaceutical and Agrochemical Data Report Writer. Ike D. Tabani, John W. Cornacchia and Robert A. Bethem. Presented at the 44th ASMS Conference on Mass Spectrometry and Allied Topics, May 12 - 16, 1996.

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Method validation studies require processing of method performance experimental data and generation of custom analytical reports.   Although there is some similarity between validation plans, (contract research organization) CRO's typically see considerable variation in design due to compound and sponsor driven requirements.  In addition to differences in experimental design, method validation report formats are often dictated by sponsor (versus CRO) standard operating procedures (SOP).  These factors complicate any efforts to streamline report generation via software automation.

One approach towards providing a flexible reporting tools to study managers has been the utilization of MS Office97 automation.  The advantage of this approach is that MS Word97 is used throughout many if not all pharmaceutical companies and FDA.  Tracking and processing of method validation trial results can be handled by a MS-Access97 database and user interface constructed with MS-Visual Basic (Visual Basic  or Visual Basic for Applications).  Report data can be queried and written into a pre-designed and preformatted  MS Word97 document templates using Access97 -SQL via MS DAO (Data Access Object) library version 3.5.  Besides enabling rapid application development, report writers also benefit from using a validated significant figure subroutines to ensure consistent numerical formatting.  This poster describes the method validation report writing module developed for ALIS-98, a LC-MS/MS data management and reporting system.

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Purpose: To evaluate the effects of regression model selection on statistical measures traditionally used to assess quantitative data set acceptability including bias of standards, r² and QC percent recovery.

Conclusion: Future work should examine procedures for outlier selection and rejection.

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The use of high speed automated analytical procedures such as LC/MS/MS in support of FDA/EPA data submissions has markedly increased over the past five years. Instrument through-put can easily exceed several hundred result records per analytical run creating the need for software capable of performing real-time post-acquisition data processing and report generation. LCMS based pharmacokinetic reports and field dissipation reports are typically method or protocol specific requiring a high degree of flexibility in the design of the report writer software. ALIS, a windows based LCMS report writer, allows the creation of study specific sample log-in screens, electronic benchsheets, and report forms customizable through an extensive set of user utilities. The ALIS report writer currently supports automated data transfer from two instrument platforms: the Finnigan XSQ 700/7000 and the Sciex API 3/300.

ALIS employs two template builders to facilitate the collection and processing of data based on study specific requirements. Method templates are created that dictate sample preparation and instrument operation parameters. Post-acquisition quantitation options are also assigned to the method template including the type of calibration curve fifting, sample response types and any result correction factors that will be applied to the data. The use of method templates greatly reduces laboratory errors due to method deviations and promotes the generation of a uniform study database.

To accommodate as many study types as possible, the ALIS user interface allows the alteration of the underlying sample descriptor database structure by the user. Allowing the user to create study specific sample log-in templates has enabled a high degree of flexibility in the back-end grouping and sorting of analytical results. Post processed data can be stored in MS Access, Oracle or any RDBMS capable of supporting ODBC. In the case of MS Office based ALIS, results data sets can be queried from Access using SQL, stored query definitions or through thin the above third party report writers.