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How feasible is the paperless laboratory? Subsequent to the recent Electronic Signatures in Global and National Commerce Act, the author examines paperless trends and their potential impact on the chemical industry.

Documentation and good record-keeping practices are key activities in the research laboratory and the chemical industry. Current trends and challenges in the industry are making document management a critical activity. Because high-volume commodities produce low profit margins, there are pressures to reduce operating costs and become more efficient, and at the same time, ensure safe operation and compliance with environmental regulations. Any systems designed to replace paper record-keeping must effectively cover and improve all the basic functions of paper systems.

Trends among chemical companies include globalization, cost reduction, and increased customer service. Effective document management addresses all three. For example, customer service is improved by personalized customer information and up-to-date sales guides.

As a result of the current trends, the “paperless system”—scanning paper documents into electronic images or inputting source data and managing this information electronically—has emerged as a way to manage documents effectively. The paperless system is intended to meet the specific needs of corporations and certain end users. Its use does not imply the elimination of all paper documents.

Paper has its advantages. After all, neither technology nor software compatibility is an issue with paper records. And in small quantities (notes, letters, clippings), paper is portable. Electronic documents, on the other hand, require far less storage space and allow large groupings (e.g., product specifications, case files, and laboratory notebooks) to be portable and more available.

Electronic signatures

One of the primary concerns within the chemical industry is the need for signatures to validate scientific reporting for intellectual property and patenting purposes, environmental compliance, and tracking equipment and inventories. Records of inventions are the basis of patents and intellectual property worldwide. Laboratory records also document details of product manufacturing for purposes of quality assurance, regulatory compliance, and consumer protection.

The paperless laboratory is even closer to a reality with the signing of the Electronic Signatures in Global and National Commerce Act on June 30, 2000 (1). The act was approved unanimously by the Senate with near unanimous approval by the House of Representatives. This law has the potential to significantly affect the way many transactions are conducted. The act generally prohibits any state from denying legal effect to a signature, contract, or other record solely because it is in electronic form, thus giving agreements entered into through the use of electronic media the same legal status as paper versions.

Similarly, if a law requires that a written agreement or other record of a transaction be retained, the act provides that the requirement may be satisfied by retaining an accurate electronic record, which is accessible for the prescribed period of time in a form that can be accurately reproduced. The act is “technology neutral”, giving parties the freedom to determine the technologies used to conduct the electronic transaction. However, the act does not limit, alter, or otherwise affect any other requirement imposed by law relating to any rights and obligations of the parties, nor does it require any person to agree to use or accept electronic records or electronic signatures.

As noted by Senator Spencer Abraham (R-MI), an original sponsor of the bill, “This legislation will eliminate the single most significant vulnerability of electronic commerce, which is the fear that everything it revolves around . . . could be rendered invalid solely by virtue of there being an electronic form.”

For an electronic record-keeping system to be valid for handling the patent process for developing new chemicals and pharmaceuticals, it is crucial that there be a mechanism for authenticating the origin of a new idea, a drug or chemical, or a new process for designing or producing a drug or chemical. This act will allow authentication of electronic records to proceed unencumbered.

Electronic laboratory notebooks

The movement toward the use of electronic laboratory notebooks (ELNs) is growing because of the need to integrate automated technology with traditional laboratory practices and Web-based technology. Corporations are providing the capital and labor to combine the functional elements of print and electronics to create a working ELN. To date, most ELN technology exists as software, which integrates the Web and automated equipment.

The skepticism about the ELN centers on the fact that laboratory notebooks are the primary repositories for R&D and intellectual property. They are used to substantiate claims within patent applications and, in the event of patent interferences, to defend exclusive patent licenses granted by patent offices around the world. They are also a key part of records management programs in R&D organizations.

To bridge the gap between traditional laboratory notebook practices and the totally electronic notebooks, laboratories are using the PatentPad by SCRIP-SAFE Security Products Inc. (Cincinnati, OH). The PatentPad allows scientists to use their laptops safely with the confidence that original data are verifiable and retrievable when needed. The system relies on a unique paper that is backed by multiple layers of documents for corroboration for each end user. The paper is not reproducible and cannot be photocopied (2).

The Collaborative Electronic Notebook Systems Association (CENSA) is at the forefront of the ELN revolution. CENSA, an international group of software suppliers from industry, national laboratories, regulatory agencies, and academic institutions, is dedicated to developing the ELN and state-of-the-art technology for electronic record-keeping systems. CENSA defines an ELN as a system with the right combination of policies, procedures, technologies, and regulations working to create, store, retrieve, and share fully electronic records in ways that meet all legal, regulatory, technical, and scientific requirements (3). CENSA has done extensive research on paper and electronic notebooks to uncover the many ways in which electronic systems benefit researchers. James D. Myers of Pacific Northwest National Laboratories commented, “It was probably inevitable, in light of the ever-increasing role of computers in the lab, that ELN would emerge as a powerful way for scientists to record their activities.”

There are two kinds of ELN: personal and collaborative. The two are distinct but share a closely linked consumer market. CENSA defines the personal electronic notebook system (PENS) as a lightweight tool that is simple enough to compete with a paper notebook and replace it in functionality. Although the PENS can conceivably include capabilities for browsing and grabbing information from online libraries, databases, other electronic devices, and remote sources such as the Web, its focus is primarily high end-user productivity for writing documents and data sets, managing data, publishing and sharing information, and creating records. The consumer market for PENS is starting to develop, and a few interesting component technologies and partial solutions are available now. The challenge will be to integrate these components in usable ways.

The collaborative electronic notebook system (CENS) supports connectivity, communication, information retrieval, and multiperson workflow. It relies on the basic capability of the PENS, but goes much further to integrate the electronic protocols of a collaborative infrastructure. The challenge is to carefully select and integrate mature component technologies that will support business activities, scientific research and discovery, auditing business operations, and reviewing engineering innovation. A formal record or report is usually produced. With an electronic notebook, the records will be published electronically and shared with collaborators, reviewers, or approvers. Once information is shared, it moves out of the personal realm into the collaborative realm.

Because the ELN is first and foremost a writing tool for the individual, it must support ubiquitous data recording, note taking, drawing, calculating, and other activities that must be documented. When used for business, it must also tie into the record-keeping infrastructure.

The benefits of the ELN

The Collaborative Electronic Notebook Systems Association (CENSA) did extensive interviews of scientists working in pharmaceutical, chemical, and biotechnology companies. From the responses, it is apparent that individuals in regulated industries expect ELNs to help ease laborious documentation of experiments and R&D processes. When CENSA asked scientists working in teams to explain what benefits they would expect from electronic notebooks, some responses were consistently voiced (4). “Make the organization’s research notebook base searchable.” “Make notebooks shareable (in real time) with peers.” “Let us have access to our notebooks while QA is checking them.” “Handle the witnessing process more efficiently by allowing me to set up pools of qualified colleagues who can witness my work.” “Help me schedule and control project resources and tasks better.” “Give me personalized views into team project data to expedite my interaction with them.” “Stop repetition of satisfactory experiments. Previous experiments should be made evident without a lot of effort.”

Scientists have broad-ranging expectations for automated systems (see box, “The benefits of the ELN”). Computer-literate scientists often ask for sophisticated computing capabilities such as integrated videoconferencing, shared windows, and project scheduling and resource management tools. In fact, for more advanced users, the ELN software is much more than just a record book—it becomes a collaborative, intelligent working environment.

After an R&D organization’s infrastructure becomes sophisticated, with intelligent agents and other programs that run on top of a highly functional and standardized set of network services, the ELN can begin to do many things for a scientist beyond the traditional notebook. In the box, “Utility of Smart Document”, an organic chemist who is running a reaction demonstrates the utility of the ELN.

Other electronic notebook developments

The Board on Chemical Sciences and Technology (BCST) is a unit of the Commission on Physical Sciences, Mathematics, and Applications of the National Academies. Established in its present form in 1983, the BCST conducts a diverse program of studies and related activities (e.g., workshops and symposia) to produce authoritative, independent recommendations about the science and technology aspects of public policy questions in chemistry, biochemistry, and chemical engineering. The board is sponsored by the National Science Foundation (Chemistry Division and Division of Chemical and Transport Systems) and the U.S. Department of Energy (Division of Chemical Sciences).

In the 1999 BCST report, David R. McLaughlin of the Eastman Kodak Co. described how the company uses computers and information technology to enhance operations in its research laboratories (5). Kodak has focused on creating an electronic or computerized laboratory and delivering information to the scientists’ desktops. To illustrate the impact of Kodak’s “wired laboratory”, McLaughlin described four advances in computing technology that have increased the efficiency of the analytical chemistry laboratory:

• automation and simplification of some of the tasks associated with analysis and synthesis,
• management of information and knowledge,
• generation and maintenance of data in electronic (digital) form, and
• data analysis and chemometrics.

Examples of components of Kodak’s wired laboratory include Quantum, an integrated spectroscopy information system; a walk-up spectroscopy laboratory with instruments online; increased capabilities for electronic access to information and analytical data; and WIMS, a Web-based information management system.

McLaughlin also described an ELN that has been developed to assist with the management of experiments, projects, and programs. He characterized the wired laboratory of the future as one in which all scientists would use an intelligent ELN linked to all of the data-generating equipment, and in which evolving analytical technology combined with data analysis techniques would reduce the time of sample preparation and data interpretation. All of these capabilities would be provided through a common Web interface. One challenge to the analytical community is to devise real-time measurements that, when displayed in virtual reality systems, will enable researchers to “see” results and better understand them. McLaughlin also noted that high-quality, reliable software at reasonable cost is one of the most critical needs.

Paper versus electronic media

There are some legitimate reasons why individuals may prefer paper documents over electronic documents. Some people find it easier to read documents or pick out specific pieces of information on paper than on a monitor; monitor resolution and lighting conditions all affect one’s ability to skim or speed read on a monitor. In many cases, formally executed paper documents must be retained as official records or for potential use in court proceedings, although that will change, now that the electronic signature law has been enacted.

On the other hand, some people prefer to review documents on monitors, especially when several similar documents are involved and when the review is for a specific purpose (e.g., has a document been signed or approved, is it on the proper form, are all required attachments present?). If appropriate technology, infrastructure, business processes (document coding and indexing, workflow, and file organization), training, and support are in place, electronic documents can be more easily transmitted (e-mail), shared (Intranet and other shared networks), and retrieved (electronic image and document management systems).

Sometimes the benefits of converting paper documents to electronic documents are marginal compared with the associated costs. The trade-offs have to be considered because many documents are discarded after initial review or after a specific piece of information has been found, for example:

• If a document arrives on paper, then it doesn’t have to be scanned and coded before it is reviewed.
• If a document arrives electronically, it must be printed, collated, and distributed for review.
• Off-site warehousing of paper documents is often the most cost-effective way to store seldom-used documents simply because it is not worth the time and expense of converting them to electronic format.

Paperless regulatory approval

One area in which the “paperless system” concept has been applied successfully is the submission of data to regulatory bodies for product registration. George Young, a senior manager with Deloitte & Touche in Detroit, said, “The savings that some companies have realized by submitting their documents to the U.S. Food and Drug Administration [FDA] electronically are enormous.” Young explained that ordinarily, agricultural and pharmaceutical firms submit reams of paper to the FDA in order to obtain regulatory approval. Traditionally, this information has been transmitted electronically and housed in multiple (computing) systems at the company. Before submission, this information has to be printed, reviewed, checked, and double-checked. Electronic submission saves the companies enormous amounts of time and money. Following the submission, the company receives instant electronic acknowledgment of receipt. In the past, paper submissions would frequently get lost.

To receive regulatory approval to market a drug, biotechnology and pharmaceutical companies must compile and submit the required documentation to the appropriate regulatory body in the country or countries where they intend to market it. These submissions are complex publications that include numerous individual documents, such as chemistry studies, preclinical studies, dosage trials, statistical analyses, and clinical-phase studies. The contents are formatted in many different programs—word processing, spreadsheets, graphics, statistical analyses, and scanned legacy documents.

Despite the variety of file formats, the publication submitted to the regulatory authority must have the identity of a single submission. It must be easy to review. For this, the publication must have advanced navigation aids, such as tables of content at the submission and major section levels. It also must contain hyperlinks that direct the reviewer to the exact page on which the cross-reference target resides. A complete new drug application (NDA) submitted to the FDA can easily exceed 100,000 pages. Submissions consisting of 400–600 volumes, each comprising hundreds of thousands of documents, can reach 500,000 pages. Some filings exceed 1 million pages. Because the individual documents contain text and graphic elements, extensive cross-referencing, indexing, sectioning into volumes, and tables of content are required.

Electronic data submission pilots

In the late 1990s, Bayer Corp.’s Agricultural Division and Isis Pharmacueticals engaged in pilot programs that helped benchmark the process for submitting data and information to regulatory agencies in Canada and the United States.

Bayer approach. Bayer’s Agricultural Division and other crop protection product companies submit millions of pages of documentation worldwide each year to register new active ingredients and product uses. The registration procedures are painstaking, involving the assembly of rigidly structured, complex publications that are needed to register and market all agrochemical products.

Until recently, most of this information was produced in multiple paper copies to meet the reviewing, archiving, and approval requirements of global regulatory agencies. Paper submissions involve many kinds of formatted documents, ranging from 30 to 5000 pages. The paper submission system is labor-intensive and expensive.

In 1997, the Canadian Pest Management Regulatory Agency (PMRA), which is responsible for registering and approving plant protection products while safeguarding human and environmental health, attempted to achieve a 40% reviewer productivity efficiency gain for its product registration process. The agency planned to meet this goal through data harmonization and electronic submission reviews.

“The PMRA is committed to improving processes and reducing costs and time associated with the review of submissions,” said Carmen Krogh, electronic initiatives project manager. “The agency proposed that pesticide registrants provide submission information in an electronic format, designed to support the submission’s efficient electronic review.”

Bayer’s Agricultural Division volunteered to participate in a pilot project with PMRA. “The timing was right because we had a compound ready for registration,” said Karen Pither, the division’s North American Free Trade Agreement (NAFTA) and international regulatory affairs manager.

Companies can choose to submit a research permit application to the PMRA, essentially a preview of the product registration. Bayer chose CoreDossier, an electronic documentation software developed by Electronic Submission Publishing Systems Inc. (ESPS; Fort Washington, PA), because it was a satisfactory commercial electronic assembly and publishing system. The research permit was submitted in June 1998 after being assembled and published in only 5 weeks.

The Bayer research permit was the first electronic submission to the PMRA, using CoreDossier to manage and assemble the publication. “Besides obtaining the permit, the goal of this research permit was to allow the PMRA to get an early look at the three different electronic formats,” said Doug Soper, senior technical information specialist at Bayer’s Agricultural Division. The submission included CADDY (Computer-Aided Dossier and Data Supply), Portable Document Format (PDF), and Web-based PDF; all three formats were prepared from one electronic assembly process.

As a parallel process, Bayer completed its research permit by paper during the pilot. “Completing the electronic submission in tandem with the traditional, paper-based method helped Bayer assess the potential efficiencies of electronic-based publishing,” said Alison Lowery, global director of chemical markets at ESPS.

In December 1998, Bayer sent the full product registration to the PMRA, including reports and summaries, several demonstration files of color images, and even a video! The three electronic formats were included, as well as paper, which is still required by all agencies.

The electronic submission of documents by Bayer has proven to be a successful application of electronic document management techniques. It saved Bayer and the PMRA substantial amounts of time and money. Bayer is now working toward fully implementing this system for paperless submission of regulatory documents to PMRA.

Isis approach. In April 1998, Isis Pharmaceuticals—a San Diego-based biotech company involved in the discovery and development of antisense drug technology—submitted the first NDA electronically to the FDA. In August 1998, the FDA granted approval to Isis for marketing Vitravene in the United States. Vitravene is used to treat cytomegolovirus retinitis, an eye infection in patients with AIDS.

To begin the process of preparing regulatory submissions, Isis used CoreDossier to electronically assemble and publish a 10-volume compendium on chemical manufacturing controls (CMCs) for the FDA. The CMCs were completed in March 1998.

Isis evaluated CoreDossier in October and November 1997 by assembling and publishing a range of sample documents produced with various graphics and statistical packages. The company then decided to license and install this software. In the meantime, Isis implemented standard templates for writing documents, training for authors to insert cross-reference hyperlinks, and standard operating procedures for releasing approved documents.

The submission quickly grew to twice the originally estimated size. Isis produced a 388-volume submission, including quality control reviews for republishing and reprinting. The Isis staff worked in shifts 24 hours a day to review, print, bind, and package the volumes. The full NDA for Vitravene was submitted to the FDA in April 1998. Isis then prepared an 80-volume marketing authorization application to the European Agency for the Evaluation of Medicinal Products in late April 1998. The approval of the Vitravene submission by the FDA was completed in 5 months.

“CoreDossier was one of the reasons we were able to meet our partner deadlines, achieve our milestones, and receive progress pay-outs,” said Lance Dong, technical product manager at Isis.

“This is an extraordinary time to market,” explained Mark Lotz, executive director of regulatory affairs at Isis. A number of factors contributed to this success, including the team effort throughout the entire organization to complete the submission. The internal review process was streamlined with the use of CoreDossier, which reduced the review time by about 4 weeks. The company expects additional efficiency gains with future submissions. “We developed an easy method of transferring a PDF file onto an online icon for departments to review, rather than copying and copying paper,” says Lotz.

“This first NDA was proof of our technology. We proved we knew what we were doing from a scientific, as well as a business standpoint,” said Dong. He further explained that the scientific discovery of such a new drug class is truly cutting-edge medicine, but the steps Isis completed on the business side were just as advanced. Isis knew that it had to try an electronic submission for an NDA. Isis used ESPS and the CoreDossier software to achieve this goal.

Paperless technology in clinical settings

Another example of paperless technology is the use of Creative Socio-Medics (CSM), a subsidiary of Netsmart Technologies (Islip, NY), in St. Vincents Psychiatric Hospital and Medical Center in Harrison, NY. St. Vincents was honored in September 2000 for developing a “paperless hospital”. Net smart Technologies developed an innovative electronic patient records system that allowed St. Vincents Hospital to become the first behavioral health facility to receive the Nicholas E. Davies Award of Excellence from Computer-based Patient Record Institute and Healthcare Open Systems and Trials (CPRI-HOST; Bethesda, MD). CPRI-HOST is a consortium of academic institutions and business groups focused on best practices in electronic medical record keeping. The award is given annually to health organizations that improve patient care through better information management.

St. Vincents has worked closely with CSM for 10 years, changing their clinical record-keeping process to a fully electronic system and, in effect, creating a “paperless hospital”. Joe Paternoster, director of behavioral health information services for St. Vincents Catholic Medical Centers of New York, says that all 250 members of the hospital’s clinical and support staff use the computer record system, the Clinician Workstation, at the private psychiatric organization’s four locations.

As a result of their efficient efforts, St. Vincents now logs more than 200,000 outpatient visits and 3000 inpatient visits a year and grosses annual revenues of $175 million. “The new system has decreased occurrences of patient chart deficiencies from 40% per month in early 1998 to 3% per month by late 1999, saved up to 10 min for each psychosocial and discharge planning assessment, and increased efficiency in meeting important corporate compliance regulations,” said Ron Marge, communications director for CSM.

Jerry Koop, CEO of CSM, a subsidiary of Netsmart, said, “St. Vincents offers a prime example of how new technology in electronic record keeping can directly translate into the most important part of health care’s delivery mission.”

He continued, “Computer-based patient records are the new frontier in health care and, as this award shows, behavioral health care. We can help a hospital become more efficient, cut unnecessary administrative costs, and save time. Ultimately, those savings can be used in the areas where a hospital should be directing its resources—providing better clinical services.”

The dawning of a new era

The Internet has forced us to think of new ways to do everything faster and more efficiently. The idea of a paperless laboratory is definitely on the horizon. We are at the threshold of this reality. The passage of the Electronic Signature Act, the Internet, and innovations in paperless technology will continue to define the reality of the paperless laboratory.

References

1. Electronic Signatures in Global and National Commerce Act. Public Law 106–229, 2000.
2. Dabeck, R. A.; Orndorff, J. CHEMTECH 1999, 29 (3), 6–12.
3. Fitzgerald, M. C. Chem. Innov. 2000, 30 (1), 52–53.
4. CENSA Web site. www.censa.org
5. Report from Workshop of Chemical Sciences Roundtable; Board on Chemical Sciences and Technology; National Academy Press: Washington, DC, Nov 1–2, 1999.

Milton Zall is a freelance writer who specializes in taxes, investments, human resources, and business issues. He is a certified internal auditor and a registered investment adviser. He can be reached at miltzall@starpower.net.