eln in the bioanalytical laboratory - atrium research feb 2012 eln in the bioanalytical... · use...

Scientifi cComputing.com 8 February 2012

B ioanalytical laboratories play a crucial role in the devel-opment of pharmaceutical drug products. Labs in large

biopharmaceutical companies typically partner with other internal groups, such as pre-clinical toxicology and clinical pharmacology, to support their analyti-cal requirements. Many, but certainly not all, of the sample analysis per-formed support pharmacokinetic (PK)

Michael H. Elliott

ELN

You have to know where you are going before you start building the road

ELN in the Bioanalytical Laboratory

and toxicokinetic (TK) studies. Some studies are exploratory, while most are drug product property measurement for regulatory submissions.

In a medium-sized company — or at a minor site of a large company — it is not uncommon to fi nd these labs also supporting discovery re-search kinetics. In even smaller opera-tions, the data generation function is most commonly fully outsourced to a contract partner, though this is, of course, a growing trend across the full spectrum of organizations.

Bioanalytical departments are under tremendous pressure to increase effi cien-cy and throughput, while at the same

time maintaining compliance with good laboratory practice

(GLP) regulations. Further adding to the stress on

operation, their scientists are ex-

pected to keep up with leading-edge instrumentation

technologies to develop new assays and improve sensitivities.

In the last few years, the drive to escalate the number of drug candidates has resulted in a growing number of pre-clinical and clinical studies. With labor being the major operational expense, increasing numbers of biological samples must be processed with the same level of staffi ng in a tight budgetary environ-ment. For an internal operation, the cost structure must be competitive with con-tract research organizations. For chemi-cally synthesized small molecule drugs, liquid chromatography/mass spectrom-etry (LC/MS) has been the dominant analytical technique for many years. For large molecule biologics, electrochemilu-minescence and fl uorescence instruments are the norm. Robotics for sample prepa-ration and technology to shorten analysis time (e.g., UPLC) has been utilized in the last few years to increase sample throughput at the bench. With the large volumes of data generated, a laboratory information management system (LIMS)

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is commonplace for sample and result management; the dominant product in this market space being Thermo Scientifi c’s Watson LIMS.

Despite the millions spent on advanced analytical technology, robotics automation and LIMS, there are process bottlenecks that must be overcome to further streamline workfl ow and reduce cycle time. One of these is the wide-scale use of paper lab notebooks for proving regulatory compliance with standard operating procedures (SOP), developing methods, solution / quality control (QC) / standard preparation, experiment docu-mentation, and other tasks. Combined with poor LIMS report automation and the paper notebook information silos, generation and reviews of study reports are also labor-intensive. Samples are rapidly processed only to have the deliv-ery of results logjammed.

Opportunities for deviations from established SOPs and the introduction of transcription and calculation errors increase with manual activities. Consequently, to minimize regulatory risk exposure, there are addi-tional delays to double-check entries, perform peer reviews, and fi nal quality assurance checks. Our analysis indicates this has a 15 to 20 percent negative impact on overall effi ciency. As sample loads increase further, additional personnel must be added to enhance capacity if there are no improvements.

Integrating electronic laboratory notebook (ELN) into the workfl ow improves sample through-put and lowers costs of compliance. This can be accomplished by:� Forcing compliance with procedures — such as a daily

balance check — and documenting proof of execution� Templates to eliminate variability between analysts� Recording user actions in an audit trail where date

times are computer recorded� Direct instrument integration (e.g., LC/MS) elimi-

nating manual transcription

� Expedited quality assurance (QA) approval, as electronic data are easier to fi nd, more legible, and records can be linked between sources

� There is no need for secondary review, as calcula-tions are automated and data are collected directly from devices like balances and pH meters

� A common inventory of chemicals, reagents and stock solutions with fl agging of expired certifi cates of analysis

� Data from the ELN (e.g. sample details, sample weights, standard concentrations) are transferred electronically to LIMS for quantitation and reporting.

MANAGING BY EXCEPTIONThe IDBS BioBook deployment undertaken by

Abbott Laboratories’ BioAnalytical department (Ab-bott Park, IL, and Ludwigshafen, Germany) specifi -cally targeted laboratory throughput as the primary

project justifi cation.1 After an analysis of laboratory processes, the department concluded that reporting and reviews were the biggest barriers to expediting FDA submissions. Robotics, LC/MS, Watson LIMS, and NuGenesis Scientifi c Data Management System (SDMS) all helped to dramatically decrease cycle

times over the last 10 years, but there was much room for improvement.

According to IT Program Manager, Dr. Yan Song, “The manual and paper-based processes added weeks to the release of a fi nal report. There were too many reviews to capture any deviations that might have been introduced.”

If a deviation from policy was dis-covered, it was addressed, and the report had to undergo yet another review cycle. The Abbott team, therefore, decided to implement a two-pronged strategy: management by exception and report automation.

Management by exception is the philosophy of only reviewing deviations from established policies. For example, instead of a quality control review of every toxicokinetic report, errors can be prevented or captured at the source. Any deviations are reviewed while the rest of the report passes through the pro-cess. Tracking nonconformities also allows manage-ment to implement lean practices to address quality and continuous improvement. ELN was, therefore, required to take advantage of its template, track-ing and audit trail capabilities. According to Song, “SOP requirements are built into ELN templates that enforce capture of required information and perform any necessary calculations. All deviations in required


ELN

Acronyms

COA Certificate of Analysis � ELN Electronic Laboratory Notebook � GLP Good

Laboratory Practice � LC/MS Liquid Chromatography/Mass Spectrometry � LIMS

Laboratory Information Management System � PK Pharmacokinetic � QA Quality

Assurance � QC Quality Control � SDMS Scientific Data Management System �

SOP Standard Operating Procedures � TK Toxicokinetic


fi elds are easily search and tabulated.” There are built-in checks to alert a user before accidentally in-troducing an error, such as warnings that a certifi cate of analysis (COA) has expired or that a balance check has to be performed. In some cases, where a deviation might be acceptable, it is fl agged for an additional review by a principal investigator.

Abbott integrated BioBook with Watson LIMS for the exchange of sample lists for preparation and the creation of LC/MS sequence fi les that are sent to the instrument for execution. At the end of a study, a report is generated from Watson using UptoData’s iStudy Reporter. A future release of iStudy Reporter will pull study data from BioBook at the same time, but for now, notebook data are copied and pasted into the auto-generated MS Word fi le. The quality assurance department will simply review the excep-tion and audit log in the ELN for any deviations, which has “eliminated weeks” from the old process, according to Song.

IMPROVING EFFICIENCYThe strategic “eLab” initiative at Johnson &

Johnson’s pharmaceutical company, Janssen Phar-maceuticals (Radnor and Spring House, PA; LaJolla, CA; and Beerse, Belgium), deployed a large number of ELN seats across all biology R&D departments. Approximately 1600 users of Accelrys’ Symyx Notebook (versions 5 and 6) are using the system to support discovery and early- and late-stage develop-ment, which includes bioanalysis. The majority of users are focused on large molecule R&D; however, the system does have some small molecule research-ers. As the ELN is used across all of groups, both regulated and non-GxP operations are supported by

the same instance, though approaches to templates and processes vary.

“Our primary objective was to increase laboratory effi ciency, followed by regulatory compliance and intellectual property protection,” said Christopher Perrotto, ELN Program Manager. When asked how they defi ne effi ciency, Perrotto indicated “this is a question we get a lot. Effi ciencies are gained by the ease of entering data in a consistent format. The ELN allowed us to consolidate processes and methodolo-gies, which resulted in faster access to data.”

Consistent data entry was supported by the imple-

mentation of over 200 ELN templates, primarily in regulated areas such as bioanalytical support of clini-cal pharmacology. Previously, that group relied on paper for setup checklists, standard and QC creation, and other procedures, while using Watson LIMS for sample and results management. Many calculations were performed by hand, which required checking by another analyst. Working with the business, IT imple-mented a series of validated spreadsheets that are operated from within the ELN experiment templates.

Perrotto said the overall level of automation is currently “pretty low” as the initial goal was


ELN

AssuranceReview

LIMS Doc Mgt

Note-Book

Analyst AExecuting

Experiments

Major Instruments

InvestigatorReporting

InstrumentLog Book

Spreadsheets

Study Report

Balances, pH, ...

Figure 1: Paper and manual processes require additional reviews


to replace paper-based processes. The ELN is not yet integrated with Watson, though Accelrys does provide an interface. “The way we use Watson is complicated. The off-the shelf interface is not as advanced as we need it to be.”

There is a tie with Agilent’s OpenLAB for accessing raw data, and the J&J team is building an interface to Titian’s Mosaic compound management system. Phase two of the project is enhanced automation; consoli-dated reporting is on the team’s roadmap this year.

“Accelrys’ addition of Pipeline Pilot to the in-frastructure exposes reporting a bit more and is a consideration for the future,” Perrotto said.

This step-wise strategy has been key to the success of the project. Perrotto expressed: “When you fi rst start talking to departments, they want everything. We learned it is better to give users functionality in bite-sized chunks, fi rst replacing the paper.” He indi-cated change management was the biggest challenge of the project. “It helped that we had top-down man-agement support. But, it was more important that the business was heavily involved and had leaders for process change. Hitting people up with too many bells and whistles upfront will negatively impact adoption. You have to accept fl exibility and that all people will not operate in the same way.”

A LIMS / ELN COMBINED SYSTEMBayer Pharma AG has embarked on an entirely

different strategy, opting to partner with a supplier to develop a comprehensive solution for their Wup-pertal, Germany location. Bayer and LabWare are working together to adapt both LabWare’s LIMS and ELN products to address the needs of the bioanalyti-cal laboratory. Currently in the pilot phase, Bayer

expects to fully validate and deploy the system within the next 18 months, replacing a custom-built LIMS.

According to Dr. Frank-Thorsten Hafner, IT Coordination for Bioanalytics, effi ciency in reporting and analysis were vital in the decision to go with a combined solution. “The automation of reports was the most important consideration of the project,” said Hafner. “We also want to perform comparison analysis between studies and methods and results of different QCs.” With an eye toward changes in future business processes, the group felt they required a system that had an adaptable architecture. “Systems specifi cally designed for this market lacked the neces-sary reporting capabilities and were too rigid in their design, so they were ruled out,” he said.

After eliminating specialized systems, the Bayer team began to look at major supplier platforms to see if they could meet their requirements. Not fi nding a general-purpose solution that offered the needed functionality out-of-the-box, the interaction with the vendor was a deciding factor.

Hafner said “LabWare was very interested in developing a system for the larger community right from the start. We did not want a one-off bespoke system, which might be diffi cult to support in the future. The team also desired a modular design that could adapt to future changes. This approach also lowers our validation effort, which was a big advan-tage.”

LabWare personnel are located at the Bayer loca-tion, and the partners are using an iterative approach. Bayer personnel specify system requirements and discuss them with template developers, which results in an early prototype. This is then reviewed by ad-ministrators of the legacy system to determine if any


changes are required. If not, the prototype is further built out and piloted with key users where decisions are made to go forward or go back and address defi ciencies.

The initial phases of the project have been sample management, reporting and calculations. For many of the analysts, the normal mode of system operation is through LabWare’s ELN, which provides an Excel-like view into specifi c calculations performed by the LIMS. LIMS will check the data against established guidelines and fl ag any exceptions. Final results can then be shared across the entire department.

“It is a big advantage for us that all our sub-de-partments are using the same database,” said Hafner.

One of the last frontiers of bioanalytical automa-tion is the streamlining of the data and information fl ow. Preventing errors at the source and ensuring consistency across analysts also lowers costs of regulatory compliance. As users report, ELN plays an essential role, though strategic goals vary, and these will dictate how it will be deployed and used.

Dr. Hafner suggests prospective users should “es-tablish a vision for the project” going on to say that laboratories should take a “roadmap approach and understand the process from sample storage through reporting.” In other words, you have to know where you are going before you start building the road.

1. Reiser, Matt; Wilson, Dave; Kim, Grace; Song, Yan; “Taking the Next Step: Bio-Analysis Lab Automation Beyond LIMS”; 9th IQPC ELN Conference, Sept 2010

Michael Elliott is CEO of Atrium Research & Consulting. He may be reached at editor@Scientifi cComputing.com

ELN


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