A Quick Guide to ELN Regulatory Requirements
Charting the best course for rapid approval and favorable review starts with conformity to several agency guidelines
Ah, for the good old days! Laboratory results were dutifully recorded in bound, hardcover notebooks. Each page was dated and signed, and numbered consecutively. An error was corrected by crossing out (without obliterating) the original entry, then signed and dated to indicate exactly who made the change, when, and (if appropriate) why. Completed notebooks were stored in dry, fireproof file rooms.
Modern electronic laboratory notebook (ELN) systems are more efficient, more flexible, and more powerful. A laboratory information management system (LIMS)1 or laboratory device can communicate directly without the need for human intervention and potential transcription errors. The ELN can perform sorts, calculations, indexing, trend analyses, and a number of other examinations never considered in the “paper” days.
Potentially, though, a careless, fraudulent, or unscrupulous scientist could change a data point by overwriting an entry in the database, leaving no obvious trail of cross outs, erasures or missing pages. Without some sort of controls, the ability to review laboratory results is potentially lost, and the ability to evaluate, track or critique data changes is destroyed.
The result of this sacrifice of control for efficiency has left regulators skeptical, and has resulted in a number of regulatory guidelines and requirements aimed at providing an assurance that electronic laboratory notebooks preserve the same level of secure controls as did their paper predecessors. Specifically, the developer of an ELN system (and, depending on application, the user of that system) should be aware of and compliant with:
• 21 CFR Part 11, the U.S. Food and Drug Administration (FDA) regulation of electronic signatures and systems
• Good Laboratory Practices, particularly the GLP focus on traceability of data changes
• Good Manufacturing Practices 2, specifically requirements for validation
• PFSB 040122, the Japanese guideline
• Annex 11, computer guidelines for the EU’s Good Manufacturing Practices
And potentially the guidelines of industry supplemental organizations:
• International Standards Organization (ISO) 9001
• Pharmaceutical Inspection Convention Scheme (PIC/S) Good Practices Guidance for Inspectors “good Practices for Computerised Systems in Regulated “GxP” Environments”
• “The Application of the Principles of GLP to Computerised Systems” (Organization for Economic Cooperation and Development)
Perhaps surprisingly, and certainly appropriate, the guidance provided by these documents and organizations is compatible: compliance with all is appropriate, practical and demonstrable.
First in relevance and in FDA emphasis among the various regulations is 21 CFR Part 11. Compliance with this relatively recent regulation requires that the ELN is audited or tested for five major criteria:3
• presence of an audit trail capable of tracking any post-entry changes to data
• preservation of data from any system-related data corruption or modification
• initial testing and validation of the software system
• archiving and recall capability of the data base
• optionally) electronic signatures that clearly identify the signature and lock and date the document or database post signing
The Good Laboratory Practices and their codification for U.S. Environmental Protection Agency contract laboratories, the Good Automated Laboratory Practices, focus attention largely on the ability of the user organization to link ELN features to developmental requirements documentation, providing a base for testing performance against intended function. The GLPs, therefore, provide supplemental guidance to 21 CFR Part 11 for the construction of test scripts and the analysis of those scripts.
The Good Manufacturing Practices of the United States are currently under revision to incorporate the key 21 CFR Part 11 principles. Currently, the GMPs add further definition to the concept of validation of an ELN system, incorporating principles of control (including standard operating procedures for use and maintenance), thus expanding validation to include management of, as well as functionality of, the system.
Japan’s Kiro Shu has released PFSB 040122, roughly equivalent to 21 CFR Part 11. Because of differences in philosophy and function, true international certification of a ELN requires conformity to three sets of regulations:
• USFDA (21 CFR Part 11, GLPs, and GMPs)
• PFSB 040122 (since Japan does not de facto accept USFDA or EMA approval)
• EU’s (EMA) Annex 11
Unique aspects of PFSB 040122 focus largely on detailed specification of the electronic laboratory notebook (or other system’s) specific functionality.
Annex 11 (Computer guidelines for the EU’s Good Manufacturing Practices) is the EMA equivalent to 21 CFR Part 11.4 It differs largely in its emphasis “Attention should be paid to the sitting of equipment in suitable conditions where extraneous factors cannot interfere with the system.” Other than this focus on electronic environmental factors, the two regulations parallel closely.
A system that meets USFDA, EMA, and Kiro Shu requirements will generally be acceptable anywhere by any regulatory authorities. Some agencies will accept these certification de jure (ANVISA, KFDA, for example); others will de facto acknowledge they utilize the same principles (TGA, SFDA, CDSCO for example). There are a few non-government groups that have provided further guidance and clarification relevant to ELNs, including one (ISO) that will certify compliance with an ELN quality system.
ISO 9001 (International Standards Organization) provides guidelines for the control of all computerized systems based upon the developer’s implementation of a quality system and careful documentation of compliance with that system. PIC/S Good Practices Guidance for Inspector’s “Good Practices for Computerised Systems in Regulated “GxP” Environments” (Pharmaceutical Inspection Convention Scheme) provides detailed testing protocols and recommendations, as well as recommendations for management of a system in development and in use. Finally, the “Application of the Principles of GLP to Computerised Systems” (Organization for Economic Cooperation and Development) summarizes common principles of system quality control and provides recommendations for the management of those systems.
Vendors seeking maximum market credibility should consider having their ELNs independently certified for compliance with US, European and Japanese requirements (as further defined by the NGO guidance). Potential purchasers of new ELNs should consider including such certifications in the Requests for Proposals, and current users of systems should apply these requirements in evaluation of their systems. Use of a system that is not in compliance risks significant delay or rejection of data collected, stored or analyzed on an ELN.
Electronic laboratory notebooks are valuable tools for the modern research, quality control or operations laboratory. Regulatory agencies have provided a variety of guidance documents to define requirements for assuring accuracy, reliability and acceptability of these ELNs. Demonstration of conformity to those requirements is the most certain path to rapid approval of submissions and favorable review of clinical and laboratory data.
1. See “Managing “Risk” In LIMS Validation”, Weinberg and Fuqua, Scientific Computing, October 2011.
2. Good Laboratory Practice Regulations, Weinberg, Informa Publisher, 2007 (fourth edition).
3. Cost Effective Part 11 Compliance for Laboratory Information Management Systems”, Weinberg, in American Pharmaceutical Review, 2003
4. http://tern-quay.com/Orange_Guide/Annexs/EU-GMP-Vol4_Annex11.pdf, accessed September 2011.
Sandy Weinberg is an associate professor of health care management, and Ron Fuqua is an assistant professor of health care management, at the Clayton State University Center for Clinical Research and Regulation. They may be reached at editor@ScientificComputing.com
Dr. Sanford (Sandy) Weinberg, a Remembrance
It is with deep sadness and regret that we must report the passing of Editorial Board member Dr. Sandy Weinberg on October 8, 2011, of a heart attack. Sandy had been a long-time contributor to Scientific Computing, in many of its permutations, and a preeminent authority on pharmaceutical and medical device regulations and quality assurance.
He served as the Director of the Institute of Entrepreneurship at Muhlenberg College, where he was also a vice-president; served as president of Weinberg Associates, later Weinberg, Spelton & Sax, which developed a number of widely used FDA standards; and currently served as the executive director of the Center for Clinical Studies and Regulation at Clayton State University in Georgia, to list only a few of his many accomplishments. Somehow he also found time to write at least 17 books and over 100 papers on regulatory topics within his 61 years. Reflecting his strong belief that one should always focus on what was truly important, namely one’s friends and family, he has been a strong participant in the Boy Scouts of America, serving on their International Committee and as an International Ambassador.
Sandy co-wrote “A Quick Guide to ELN Regulatory Requirements” with Ron Fuqua shortly before his death. He will be sorely missed.