How to Predict the Future of 21 CFR Part 11
How to Predict the Future of 21 CFR Part 11
In March of 1997 the FDA issued final Part 11 regulations that provide criteria for acceptance by the FDA of electronic records, electronic signatures, and handwritten signatures executed to electronic records as equivalent to paper records and handwritten signatures. After Part 11 became effective in August 1997, significant discussions did start amongst industry, contractors, and the Agency concerning the interpretation and implementation of the regulations. While initial FDA guidance documents indicated a very broad scope with significant problems to fully implement Part 11, in 2003 the FDA released a new guidance promoting a more narrow scope. The FDA also announced to rewrite the regulation itself. This was scheduled for 2005 but has been delayed until second half of 2006.
Most interesting question is what the changes will be such that the industry can be prepared.
The future of Part 11 is easy to predict through looking
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Looking at changing of FDA’s approaches through:
– management directions
– guidance documents
– enforcement practices
The current regulation (1) as released in 1997 used a very wide scope for Part 11 as defined in sect. 11.1 “This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to the agency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if such records are not specifically identified in agency regulations.” Electronic records have been defined as “Any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system”. No distinction was made between the type of records or their criticality.
Early interpretations
Interpretations by FDA staff
Part 11 was quite confusing and the industry requested interpretations from the FDA. Because of lack of official FDA documents initial interpretation came through conference presentations and interviews with FDA staff. Although presenters made it clear that whatever they say is their own opinion and does not reflect FDA’s policy it was perceived as such. Part 11 was interpreted broadly. Examples are presentations and Q&A session with Paul Motise (2) who was part of FDA’s Part 11 development team and Christine Nelson (3). In principle Part 11 compliance was required for records that have passed any computer and the FDA could ask for such records at inspections. This included printed word documents (Print outs do not exempt from Part 11, Ref 2) no matter on . With this very broad interpretation full implementation turned out to be very expensive and for some applications impractical
FDA Guidance documents
From 200 to 2002 FDA released five Part 11 industry guidances. They all were in line with the broad scope of Part 11. As an example the guide for electronic archiving (6) suggested reprocessability throughout the required records retention period that could be 10 or more years: “Throughout the records retention period, the ability to process information in an electronic record should not diminish. By being able to process the information, you would maintain the ability, for example, to effectively and efficiently reconstruct events, detect and investigate problems, detect trends and assess the need to modify procedures or specifications to improve product quality, safety, and effectiveness.” And: “Maintaining an electronic record in a form that permits the record’s information to be processed should help you to meet the part 11 requirement that you be able to generate electronic copies of electronic records that are suitable for FDA inspection, review, and copying.” Again, the guide did not distinguish between different types of records.
Warning Letters
The FDA started to enforce Part 11 in 1999. Example: – review of your electronic complaint files reveals they have not been properly validated, there is no ability to generate accurate and complete copies of records in human readable and electronic form, there is no protection of records to enable their accurate and ready retrieval, access to your system has not been limited, as well as other significant deficiencies. .We strongly encourage you to perform a thorough and complete evaluation of all your electronic records in accordance with 21 CFR Part 11 as well as any guidance generated by FDA to assure conformance to our requirements. Do not limit your evaluation solely to the examples cited above. Only electronic records and electronic signatures that meet 21 CFR Part 11 may be used to satisfy the requirements of 21 CFR 820.198. (5)
Industry Problems
The regulation and early interpretations made made no distinction between the type of records or their criticality. Part 11 compliance was requested for all such records that have passed any computer and the FDA could ask for such records at inspections. With this very broad interpretation full implementation turned out to be very expensive and for some applications impractical. Major problems have been:
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Wide scope: Part 11 was required for all electronic records that exist in FDA regulated environment. This makes implementation very expensive. Examples included word processing systems and graphics packages.
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For some systems technical controls such as e-audit trail are not available. Availability of software with part 11 functionality was a problem for some manufacturing equipment but also laboratory equipment that was not mainly designed for FDA regulated environments.
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Long term archiving and ready retrieval including raw data and metadata combined with the requirement for instant retrieval and reprocessing over a time span of 10 and more years is difficult and some times not possible.
The FDA changes the approach for Part 11 as part of the 21st century drug cGMP initiative. The approach has been broadly introduced to the public through management presentations, a new Part 11 guidance document, and panel discussions with FDA’s Part 11 experts. The FDA also formed a Part 11 task force with the goal to collect inputs an make a proposal for a new revision of part 11.
Management directions
FDA’s 21 new approach was presented as part of FDA’s Drug cGMP initiative for the 21st century by Mark B. McClellan, MD., PhD; Commissioner of Food and Drugs, Janet Woodcock, MD, CDER Director, David Horowitz, Director of CDER’s Office of Compliance and Joseph Famulare, Director, Div. of Manufacturing & Product Quality Office of Compliance, CDER/FDA. One key point of the initiative was to promote science and risk based compliance to focus compliance efforts towards processes that have a high risk on product quality and patient safety. Joseph Famulare explained FDA’s new approach for Part 11 (6)
New Part 11 guidance document
All current FDA Part 11 guidances have been obsoleted and FDA’s new approach for Part 11 has been documented in a new Part 11 industry guidance: Scope and applications (6). The requirement of predicate rules for specific records together with the risk based approach has been suggested to define major part 11 controls, for example, validation, electronic audit trail, electronic copies and record maintenance. For example the guide recommended for validation: “We recommend that you base your approach on a justified and documented risk assessment and a determination of the potential of the system to affect product quality and safety, and record integrity. For instance, validation would not be important for a word processor used only to generate SOPs.” And for audit trail it states: “We recommend that you base your decision on whether to apply audit trails, or other appropriate measures, on the need to comply with predicate rule requirements, a justified and documented risk assessment, and a determination of the potential effect on product quality and safety and record integrity. ” The guide also recommended to look at a company’s business practice which means for audit trail: “Audit trails can be particularly appropriate when users are expected to create, modify, or delete regulated records during normal operation”.
Guidance document for using computers in clinical trials
In 2004 the FDA introduced new Guidance on Using computers for clinical trials (7). Although the guidance is for a specific application, it documents FDA’s thinking for all regulated industries and the guide is very much in line wit the Part 11 guidance as explained above. The FDA did go one step further regarding the risk assessment and the importance of the likelihood that records may be changed: Firms should determine and document the need for audit trails based on a risk assessment that takes into consideration circumstances surrounding system use, the likelihood that information might be compromised, and any system vulnerabilities. This guidance also described other options for audit trail besides computer generated electronic audit trail.
Presentations by FDA staff
FDA’s new approach was also presented at conferences, industry trainings and in panel discussions. For example, John Murray explained the importance of data record integrity and that industry should describe the tools rather than the FDA prescribing it (Ref 5): “No matter what the record it, whether paper, electronic, plastic or carbon stone, we require the integrity and trustworthy of that record. We are going to open the scope of that. We are going to allow the manufacturer developing the process on doing that control rather than prescribing it through regulations or guidance documents The problem or concern is still the same: the integrity of records. We are adjusting the solution to meet the needs of industry and technology”. Murray also explained the definition of an electronic record according to FDA’s old and new interpretation: “According to the old interpretation the mere existence of electronic data in or around a product or plant was considered to be an electronic record of the rule. This is the wrong focus. You have to go back to the predicate rule and the regulation. and then you go back and determine Part 11 controls”.
Enforcement practices
While there have been many FDA warning letters citing Part 11 before 2003, this has changed with FDA’s changing approach for Part 11. With few exceptions deviations in warning letters and FDA 483 inspectional observations don’t quote Part 11 but refer to predicate rules. Computer systems and electronic records are still subject to inspections, but in general there are fewer deviations warning letters. This is also a result of FDA’s announcement in March 2003 to review warning letters in FDA’s headquarters. As FDA’s David Horowitz said: “There will be fewer warning letters, but they will speak louder.” (11) Most likely this situation will not change before the new Part 11 will be released, but we would expect a change after it’s release.
According to FDA officials, a draft of the New Part 11 will be released in 2006. This was announced by George Smith during the Annul Meeting of GAMP America in March 2006 during his Part 11 presentation: : Where we were, Where we are, Where we are going. Based on history, current development and FDA’s most recent presentation we would expect:
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The new regulation and guidance will be in line with the current Part 11 Guidance: Scope and Applications
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Focus will be on predicate rules and risk assessment
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Risk assessment should to be justified and documented
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Enforcement discretion for for legacy systems will go away and will be substituted through risk based approaches
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Enforcement discretion for validation, electronic audit, electronic copies and record maintenance will go away and will be substituted through risk based approaches
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Industry will have more choices to define approaches to ensure integrity and trustworthiness of data. This means the strict requirement for computer generated electronic audit trail will go away.
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The process to ensure integrity and trustworthiness should be well designed, justified and documented for each individual application.
Labcompliance conducts an audio seminar: How to prepare your organization for the ‘New Part 11‘. The focus will be on #7.
Below are some photos of Part 11 related events with FDA participation
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From right to left: Martin Browning from EduQuest Inc, Paul Motise from the US FDA, Kathryn Davidson from Baxter Healthcare, INC, and Ludwig Huber from Hewlett-Packard at the IVT panel discussion in Washington DC on Learn where industry is having difficulties with compliance
1999 |
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Paul Motise (second from left) with the speaker panel at an IVT conference in Washington (2002). Other speakers, from right to left: Chris Reid, Rebecca Fuller Heyde, Jeff Beck, and Ludwig Huber
2002 |
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Mark B. McClellan, MD., PhD; Commissioner of Food and Drugs, Janet Woodcock, MD. ; CDER Director David Horowitz, Director of CDER’s Office of Compliance, Joseph Famulare, Director, Div. of Manufacturing & Product Quality Office of Compliance, CDER/FDA
FDA management explained FDA’s 21st Century Drug cGMP initiative and the impact of part 11 2003 |
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John Murray (left) at the IVT Computer System Validation Conference
Mr. Murray explained FDA new expectations for computer validation and electronic records: good engineering to ensure integrity of records Ludwig Huber (right) gives recommendations on how to implements FDA’s new approach for Part 11 2004 |
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George Smith, FDA’s national Part11 expert, at a panel discussion with Ludwig Huber during an IVT
Smith answered questions about current status and future of Part 11. Smith and Huber discussed and answered questions about computer system validation and e-records. 2005
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Joseph Famulare, Acting Director of FDA’s CDER at the cGMP training in China in April 2006. Famulare talked about current status and future developments of Part 11
2006 |
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The speaker panel during a Q&A session at the CGMP training in Beijing, May 2006. Speakers answered questions related to Part 11 and other FDA regulations. From left to right: Robert Doran, Eric Henrikson, Joseph Famulare, Nicolas Buhay (all FDA) and Ludwig Huber (Agilent Technologies and Editor of Labcompliance)
2006 |
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Learn from the convenience of your desk |
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21 CFR Part 11 Draft Guidance Document: Maintenance of Electronic Records
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FDA warning letter (For Usersclub Members, Non-members can preview)
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Joseph Famulare, FDA’s New Approach for Part 11, Video Clip
(For Usersclub Members, Non-members can preview) -
John Murray, Industry should define tools for data integrity
Video clip, for Usersclub Members, Non members can preview -
John Murray: Old and new definition of electronic Records
Video clip, for Usersclub Members, Non members can preview -
David Horowitz, FDA, Warning Letters will Speak Louder
Video clip, for Usersclub Members, Non members can preview -
George Smith, FDA, Part 11: Where we were, Where we are, Where we are going
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Strategies to Define Part 11 Scope and Controls
