Electronic Signatures & Electronic Records 16 Mar 1999

Interpretations of Part 11 That Require More Discussion

PREMISE:

In 1990, members of the pharmaceutical industry initiated efforts to obtain FDA approval of
electronic signatures in order to accelerate the industry’s ability to utilize and benefit from new
automation technology. Enabling regulations, in the form of 21CFR §11 became effective on
20 August 97. Since then, many useful FDA interpretations of Part 11 have been provided. A
specific few of the FDA interpretations are deemed to overemphasize the need for fraud
detection, and consequently to be unnecessarily inhibiting to implementation of the new
regulation; three such FDA interpretations* are addressed herein and are accompanied by
recommended remedial measures. [*All FDA interpretations referred to in this paper, including
the many that have proven extremely helpful, were provided by Mr. Paul J. Motise, who was
instrumental in the creation of Part 11 and is FDA’s most recognized spokesman on the subject.]

The three issues discussed below are:

1. Mandating use of local time-stamping to prevent fraud;

2. Level and nature of detail specified for electronic data that must be archived; and
3. Insistence on integrating electronic audit trails directly with electronic records.

The fact that transition issues associated with legacy systems are not adequately addressed in
Part 11 exacerbates the problems created by the three FDA interpretations being addressed.
Neither the industry nor the FDA apparently appreciated the importance of Part 11 providing for
a transition from existing to new systems; this oversight may have resulted from the effects that
new technological evolution is having on speed of system obsolescence. Nonetheless, validated
legacy systems need to be considered.

ISSUES:

1. Use of Local Time Stamping to “Prevent Fraud”:

Problem Statement: Requirement for universal use of local time presents obstacles in certain
situations involving systems that operate over multiple time zones, and for which use of local time
offers no advantage.

FDA interpretations state that use of local time:

1.1 is mandatory; and

1.2 is designed and needed primarily to prevent fraud.

Part 11 Preamble 101 states that “The agency advises . . .local time is the one to be recorded.”
Part 11 regulations do not mention local time.

An Industry view is that regulations are intended to prescribe what is to be done; not how to do it.
Part 11 appears to satisfy such intent. Neither Part 11 regulations nor its preamble appear to make
local time mandatory, nor should they.

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Interpretations of Part 11 That Require More Discussion

Traditionally, local time is used almost universally in such documents as batch records, whether
electronic or paper-based. Plant operators who are involved with batch records typically have
access to clocks and watches, and are therefore conscious of local time. Times entered manually
into computerized batch record systems should be local time to minimize entry errors.

In the case of a large, multinational firm operating simultaneously in six different time zones with
all its finished product inventory controls synchronized to Coordinated Universal Time (UTC),
there is neither need nor reasonable rationale for requiring use of local time for system-generated
time stamps. The firm’s written inventory reports (electronic and paper-based) can carry UTC
values without compromising the audit trail that requires only: 1) a reference time; and 2) the
physical location for a transaction to provide for future expression of the local time; should that
become necessary.

A second illustrative case involves a small U.S. firm with a legacy LIMS system that collects
instrument data and human entry data electronically. Functional specifications of the system provide
for bilateral identification and date-stamping, but lack automated time stamp capability. The system
was validated several years ago and has been maintained in a validated state. Provisions include
local time data entry by the laboratory technician when time data are significant. Mandating the use
of local time-date stamping would require a new system to be purchased and validated, without
economic benefit to the firm.

In both of the above cases, the only argument for requiring automated local time-stamping appears
to be that of minimizing chances of fraud, which is not the primary stated purpose of Part 11. With
time, evolution of new technology, along with typical system obsolescence, seem likely to make
automated time-stamping more universally available even to small firms. Meanwhile, FDA should
temper its interpretations and enforcement with reasonable levels of flexibility to avoid economic
impacts out of proportion to possible benefits. Firms should proactively seek opportunities to
upgrade systems to Part 11 compliance, including accelerated system replacement, when resources
permit.

In the case of automated systems that are networked into multiple time zones, consistency and
accuracy of time is becoming increasingly important to facilitate accurate analysis of a network
audit trail. In such situations, the need to provide an accurate time reference (e.g. UTC) to local
stations probably deserves more regulatory emphasis than does the presumed need for use of local
time. System clocks in personal computers, for example, often have errors of several seconds per
day and will accumulate substantial error if not periodically adjusted.

Another major reason foreign multinational firms oppose a commitment to local time is that, when
Daylight Savings is involved, system clocks would be required to be reset twice annually; a
measure that could be both disruptive and potentially risky to process state-of-control.

A final illustrative example for opposing mandated local time has been offered by a Swiss Quality
Assurance Executive who often travels to Australia. While in Australia, he might receive a call that
his electronic signature is needed to approve a new procedure. By entering Australian time, the
procedure will later appear to have been approved by QA before the author signed it.

Use of local time is and should remain optional to the regulated industry.

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Interpretations of Part 11 That Require More Discussion

2. Electronic Data Required to be Archived

Problem Statement: Requiring the archiving of electronic records for the sole purpose of
“preventing fraud” is wasteful. Requiring the archiving of “raw and original data” without
providing clear and practical definitions of such terms is confusing. Both kinds of interpretations
discourage or retard the industry’s use of new technology.

FDA interpretations on electronic records seem to call for including, in the raw and original data
that must be archived, every possible electronic record that might be created during an operation,
while offering ambiguous, controversial, or impractical definitions of raw and original data.

Coincidental FDA interpretations disparage the use of hybrid systems*, while acknowledging that
hybrid systems are not prohibited by Part 11. [*Hybrid systems are semi-automated systems that
contain both electronic and paper-based records.] The same interpretations imply that a mixture of
paper-based and electronic records is less than acceptable.

At present, virtually all batch records and laboratory chromatography systems are hybrids. So long
as the systems and corresponding records are designed to be seamless across interfaces between
human intervention and automated activities, such systems can be both GMP-compliant and
consistent with stated requirements of Part 11.

As an illustrative example, in the case of liquid chromatography (LC), FDA has appeared to assert
that archiving of electronic audit trails for interim steps in data analysis is as important as those
electronic records that are directly associated with creation of the final chromatogram. The
rationale given is that such trails prevent false repudiation of electronic identifications of personnel
involved: i.e., “prevent fraud.”

An Industry view is the electronic records that should be archived are those that will permit an
accurate reproduction of the chromatogram in a manner that can be traced reliably to the actual
scientific data originally collected. Interim steps not directly related to production of a final
chromatogram and that do not alter the first digital data add no substantial value to the audit trail.

Definitions of the terms “raw data” and “original records” have been subjects of circular and
seemingly endless debate for years, debates that have become further compounded by evolution of
electronic technology. A common contemporary definition for raw data in the semiautomated LC
case is “the first digital data that can be printed or saved to a recording medium,” ( this matches
well with the Part 11 definition of electronic records as a “digital form … by a computer system.”)
Since generation of the final paper chromatogram involves subjective human intervention, it follows
that all of the electronic set-up and baseline adjustment data also need to be regarded as raw or
original data to be archived. Under such definitions, an “instant replay” can be conducted at any
future time to recreate an identical copy of the chromatogram. Analogous pragmatic definitions of
raw data and original records can be applied to most situations that involve electronic records and
signatures.

Industry does not dispute the need for reliable audit trails that show who did what and when they
did it; however, FDA interpretations, in attempting to prescribe in detail how all audit trails are to

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Interpretations of Part 11 That Require More Discussion

be maintained have confused, rather than clarified the issues. Definition of measures for actually
creating audit trails can be, and should be, left to informed industrial practitioners. FDA can
facilitate progress on Part 11 compliance by engaging in frequent, detailed discussion with industry
experts about the specific issues associated with individual hybrid and legacy systems. The industry
does not create most of the software and hardware it uses; the results of such discussions can
stimulate industry and its suppliers to cooperatively resolve understood problems.

3. Integrating Electronic Audit Trails with Electronic Records

Problem Statement: A requirement that audit trails be designed for optimum fraud prevention and
inspection convenience would impose an unreasonable burden on firms that already have validated
legacy systems with effective, but less sophisticated, audit trail measures in place.

FDA interpretations imply that Part 11 requires direct integration of electronic audit trails with
electronic records, allowing no latitude for legacy systems that lack such integration, but rely on
parallel audit tracking.

An Industry view holds that non-integrated audit trail measures, electronic, paper-based, and
hybrid, have been in use for years that can satisfy requirements of good business practice as well as
GXP* compliance [*GXP = GMP + GLP + GCP regulations]. Contemporary measures exist in
various forms, some of which rely partially on human intervention. Although such measures may
not represent the ultimate in optimizing fraud detection and inspection convenience, they provide
reasonable audit histories that are commensurate with those provided by equipment logs, laboratory
notebooks, and other long-accepted practices.

One of today’s most reputable and widely-used software products for statistical analysis does not
currently contain integrated audit trail programming. Yet, many law-abiding firms have used such
software for years, while implementing their own well-established systems to provide practical and
reliable archive records describing who-did-what-when.

At the other extreme, a Quality Assurance auditor from a multinational firm recently inspected a
new LIMs system in which “full audit trail” provisions had been included, according to FDA’s
recent and controversial interpretations of Part 11. The auditor’s first look was on the 3rd day of his
inspection and was shocked to find that more than 5,000 entries had already been made to the brand
new audit trail. On the 5th day, at the audit close-out review, the lab manager reported the audit trail
had grown to more than 15,000 entries and was considered too cumbersome to be of practical use.
It would certainly prevent fraud, since anyone using it would be too busy trying to figure out what
to do with the mountain of electronic data being compiled to accomplish anything else. But, to
serve its intended purpose, the automatic archiving system would need to be redesigned.

It is recognized that technology for seamless, integrated, time-stamped electronic audit trails exists
and is becoming increasingly available in commercial systems. Such technology is also evolving in
ways that include practical configuration parameters. After a few years of transition, this whole
issue seems likely to disappear, but only if regulatory interpretations focus on what is to be achieved
and let the more experienced and responsible industry continue to define how to do it.

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Interpretations of Part 11 That Require More Discussion

4. The Case for Fraud Prevention

Fraud cannot be totally prevented, only minimized. Minimizing fraud by elaborate design of
electronic systems does not compare in effectiveness with minimizing fraud by proper management.

The stated primary purpose of Part 11 is to permit and encourage the use of new electronic
technology that was not available when current GXP regulations were created. Worthwhile, but
secondary objectives of Part 11 are to minimize fraud and facilitate FDA inspections and audits.

Most practitioners from Industry welcome Part 11 and consider it a reasonably well-written
regulation. Most practitioners also appreciate the many useful interpretations of Part 11 that FDA
has provided. The only basic objections are to those interpretations that over-emphasize fraud
prevention to an extent that makes compliance impractical or impossible. While it is recognized
that such advisory interpretations are unofficial and non-binding, unless they are challenged, such
opinions sometimes tend to become de facto law.

5. Summary & Recommendations

Part 11 is a valuable and needed enabling regulation that has, unfortunately, not provided for
legacy systems. FDA has responded to numerous requests for interpretive advice concerning
various portions of Part 11. Most of FDA’s responses have been helpful and clear; however, a few
that appear to require further discussion are addressed in this paper, since these few interpretations
are actually discouraging some firms from implementing Part 11.

It is believed the following measures by FDA would remove most existing obstacles:

a) Emphasize the use of accurate, traceable time standards for electronic records while
recognizing that accurate local time is often a good choice but not the only possibility.
b) Encourage firms to use written policies with their own definitions of original and raw data that
form electronic records, so long as those definitions satisfy GXP-related requirements;
c) Permit alternative audit trail measures for validated legacy systems; and
d) Acknowledge realistic existence and usefulness of seamless hybrid systems and provide
guidance for dealing with them.

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Interpretations of Part 11 That Require More Discussion

Appendix 1 - Reference Excerpts from Part 11

Issue 1 – Time Stamping:

§11.50(a)(2) – (a) Signed electronic records shall contain information associated with the
signing that clearly indicates all of the following:

(2) The date and time when the signature was executed;

Preamble 101 - . . .The agency believes that it is vital to record the time when a signature is
applied. Documenting the time when a signature was applied can be critical
to demonstrating that a given record was, or was not, falsified. Regarding
systems that may span different time zones, the agency advises that the
signer’s local time is the one to be recorded.

Author Note – Except for the preamble advisory statement, no mention is made of local
time.

Issue 2 –Electronic Data to be Archived

§11.10 – Persons who use closed systems to create, modify, maintain, or transmit electronic
records shall employ procedures and controls designed to ensure the authenticity, integrity,
and, when appropriate, the confidentiality of electronic records, and to ensure that the signer
cannot readily repudiate the signed record as not genuine. Such procedures and controls
shall include the following: . . .

Issue 3 - Integrating Audit Trails with Records

§11.10(e) – Use of secure, computer-generated, time-stamped audit trails to independently

record the date and time of operator entries and actions that create, modify, or delete
electronic records. . . .

Objective of Part 11:

Preamble XVI. Analysis of Impacts

A. Objectives The purpose of this rule is to permit the use of a technology that was not
contemplated when most existing FDA regulations were written, without
undermining in any way the integrity of records and reports or the ability of FDA to
carry out its statutory health protection mandate. The rule will permit regulated
industry and FDA to operate with greater flexibility . . .

Kenneth G. Chapman
Paul F. Winter, Ph.D.

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