21 CFR Part 11 -
Electronic Records and Electronic Signatures
Frequent speaker and chair person at FDA, ISPE, PDA, USP. IVT,
ECA and GAMP conferences and workshops
FDA's national Part11 expert, at a panel discussion with
Ludwig Huber during an IVT conference 2005
Smith and Huber discussed and answered questions about
computer system validation and e-record
For Dr. Huber's connection with the FDA,
2-Day Seminar with Workshops, With Dr. Ludwig Huber
In 1997 the United States Food and Drug Administration
(FDA) issued a regulation that provides criteria for acceptance by the FDA of
electronic records, electronic signatures and handwritten signatures (1). This
was done in response to requests from the industry. With this regulation, titled
Rule 21 CFR Part 11, electronic records can be equivalent to paper records and
Such a regulation was important because electronic data
handling offers noteworthy benefits in the manufacturing area and also for the
huge amount of data generated in analytical laboratories. The use of fully
electronic data acquisition, evaluation, management and archiving promises major
improvements in the workflow.
The development of the rule was initiated around 1990 by
the US Pharmaceutical Manufacturing Association (PMA, now Pharmaceutical
Research and Manufacturing Association, PhRMA). Shortly after that the PMA and
also the US Parental Drug Association (PDA) formed technical groups to address
the subject. Industry representatives met many times with the FDA's task force
under Paul J. Motise to determine how to accommodate paperless record systems
under the current Good Manufacturing Practice (cGMP) regulations. The task force
recommended publication of an “Advanced Notice of Proposed Rulemaking” (ANPRM)
to obtain public comments on the issues involved.
The ANPRM was published in 1992. The FDA requested and
received comments on a number of concerns. In 1994 the FDA published the
proposed rule that incorporated many of the comments received to the ANPRM.
Again, the FDA received comments from individuals, manufacturers and trade
associations on the proposed rule. Finally, the rule became effective on Aug
20th, 1997 as 21 CFR Part 11. The rule is available on the FDA's website
The new rule has high visibility and is the subject of
discussion not only in the United States but also in many other countries. There
are two reasons:
- Many pharmaceutical companies located outside the US
export drugs to the US market, and as such they have to follow US
regulations. The FDA can inspect these companies according to US
regulations. In case of non-compliance, the company is not allowed to export
pertinent drugs to the United States, which can have a tremendous business
- Other countries have similar issues with electronic
submissions and may use the US rule as a guideline for their local
regulation. For example, in Japan a regulation on electronic signatures and
records was released in April 2005.
Recent Warning Letters and 483's Related to Computer
Validation and Part 11
With Case Studies to Avoid and Respond to 483's and Warning Letters
The use of electronic records is expected to
be more cost effective for the industry and the FDA. The approval
process is expected to be shorter and access to documentation will
be faster and more productive. Currently the use of electronic
records as well as their submission is voluntary. Despite this
voluntary character, pharmaceutical companies are already trying to
implement the rule as quickly as possible because of three primary
1. In many situations using computers cannot be avoided,
for example in analytical laboratories for automated data acquisition and
evaluation. In this case the laboratories “must” comply with Part 11.
2. There may come a time when the FDA will no longer
accept paper records and; Electronic records have some significant advantages
vs. paper records: tangibly lower space requirements and easier retrieval are
just two of those advantages.
The rule applies to all industry segments regulated by the
FDA that includes Good Laboratory Practice (GLP), Good Clinical Practice (GCP)
and current Good Manufacturing Practice (cGMP).
The rule has an impact on all FDA regulated industries
that use computers for regulated activities.
Requirements of Part 11 are:
- Use of validated existing and new computerized
- Secure retention of electronic records and instant
- User-independent computer generated time-stamped
- System and data security, data integrity and
confidentiality through limited authorized access to systems and records.
- Use of secure electronic signatures for closed and
- .Use of digital signatures for open systems.
- Use of operational checks.
- Use of device checks.
- Determination that the persons who develop, maintain
or use electronic systems have the education, training and experience to
perform their assigned task
Implementing Part 11 has a significant impact on the
instrumentation, the work processes and on the people in operations such as
quality control laboratories and manufacturing operations.
- ·The current process of generating signatures has to
(Who has to sign what and when?).
- New procedures have to be developed in the company
and in the laboratory for limited authorized access to systems and data (Who
can do what?).
- Computerized systems used for implementation must be
updated or replaced to ensure correct functionality.
- The manner of using and handling I.D. codes and
passwords as a basis for “legally” binding signatures may have to be
- New specialists, for example, “electronic
archivists”, may be required.
Although the rule is well-documented and the FDA gave an
interpretation to 130 industry comments in their preamble, corporate IT
professionals and analysts in laboratories are often unsure when it comes to
implementation. Although in some areas the regulation is very specific, for
example, it not only requires an electronic audit trail to demonstrate data
integrity, it also specifies some attributes, but in other areas it leaves a lot
of room for interpretations, for example, about the scope of Part 11. The
biggest problem is finding a compromise between doing too much and satisfying
Frequent questions are:
- Exactly which records should be retained? (Especially
when data has to be re-evaluated several times before it can be finally
- When do we need computer generated audit trails and
how do we implement them? What should be tracked and after which entries
does the user of the system have to confirm the entries as being logged?
- How do you bind electronic and handwritten signatures
with the electronic records?
- What do we do with existing computer systems that
don't have the appropriate functionality?
- What records should we archive: original electronic
records, standard files such as PDF or XML, or can we make printouts and
delete the electronic records?
- The FDA promotes risk-based compliance, what does
this mean for Part 11?
This ´tutorial will give an overview on key requirements
and discuss the FDA’s new and narrower approach and the scope of Part 11. In the
second part it will discuss specific requirements more in detail, for example,
validation and long-term archiving and retrieval of electronic records. We will
also discuss specific applications, for example, using the Internet and Intranet
and Excel applications in FDA regulated environments.
A clear understanding of the terminology is of utmost
importance for a common understanding of the rule and its implementation.
Therefore we will dedicate this chapter to terminology. All quotations come from
21 CFR Part 11 (1).
Electronic records are "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
A closed system is defined as an environment in which
system access is controlled by persons who are responsible for the content of
electronic records that are on the system.
An open system means an environment in which system access
is not controlled by persons who are responsible for the content of electronic
records that are on the system.
Practically all systems in analytical laboratories are
closed systems. With an appropriate security system in place, the laboratory has
full control on who will access the system. An open system in a laboratory would
be one where the data is stored on a server that is under the control of a 3rd
party. Other examples for open systems are websites where everyone has access.
An electronic signature is "a computer data compilation of
any symbol or series of symbols executed, adopted, or authorized by an
individual to be the legally binding equivalent of the individual's handwritten
Electronic signatures are the electronic equivalent to
handwritten signatures on paper. They may be based on biometric identification
methods like fingerprint scanners or facial and voice recognition, but a simple
combination of a user I.D. and password is also sufficient. Within a company,
the user I.D. must be unique to a specific person. Electronic signatures are
sufficient for closed systems.
A digital signature is "an electronic signature based upon
cryptographic methods of originator authentication, computed by using a set of
rules and a set of parameters such that the identity of the signer and the
integrity of the data can be verified".
Digital signatures are required for open systems and as
such need higher security levels. Therefore, in addition to electronic
signatures, cryptographic methods have to be applied for authentication of the
user and integrity of the record.
Biometrics is "a method of verifying an individual's
identity based on measurement of the individual's physical feature(s) or
repeatable action(s) where those features and/or actions are both unique to that
individual and measurable".
Examples of biometrics include facial recognition, voice
recognition and fingerprint scanners. Most of them need specific hardware and
software. The biggest problem with such devices is validating that they work
reliably for the specified user but not for anyone else.
Hybrid systems are a combination of electronic records and
paper records. They are common systems in analytical laboratories today. Raw
data are recorded electronically to reconstruct the analysis but the final
results are printed and signed on paper. The FDA does not prohibit hybrid
systems but has expressed some concerns about their acceptability.
Meta data is important for reconstructing a final report
from raw data. In chromatography it includes integration parameters and
Predicate rule as referred in 21 CFR Part 11 are the 21
CFR Food and Drugs regulations (besides 21 CFR Part 11). They are basically
promulgated under the authority of the Food, Drug and Cosmetic Act or under the
authority of the Public Health Service Act.
t Specifications for Software and Computer Systems
Requirements of the Rule
21 CFR Part 11 includes 36 pages out of which only 3 pages
constitute the rule itself, the other 33 pages are a preamble with comments from
the FDA on feedback from the industry. Part 11 has a total of 19 requirements.
Some of them are specific to Part 11, others are more generic requirements of
some or all FDA regulations. In this section we list the most important
requirements and give some interpretations for implementation.
System Validation - 11.10(a)
"Procedures should be in place for Validation of systems
to ensure accuracy, reliability, consistent intended performance, and the
ability to discern invalid or altered records".
That condition applies to both new and existing systems.
This is nothing new for operations using computers in a regulated environment.
Validating computer systems has been very well described and most companies have
developed strategies for implementation. The problem lies not as much with new
or fairly new systems but more with older systems. They require a formal
evaluation and a statement on their validation status. If an older system cannot
be validated it should not be used under 21 CFR Part 11. Information on
validating software and computer systems can be found in References 2 and 3. The
extent of validation depends on the complexity of the system and impact of the
system on product quality and data integrity.
Validation should include application specific functions
as well as functions related to Part 11, electronic audit trail and electronic
signatures. Recommended test procedures include:
- Limited and authorized system access. This can be
achieved by entering correct and incorrect password combinations and
verifying if the system behaves as intended.
- Limited access to selected tasks and permissions.
This can be achieved by trying to get access to tasks as permitted by the
administrator and verifying if the system behaves as specified.
- Computer generated audit trail. Perform actions that
should go into the e-audit trail according to specifications. Record the
actions manually and compare and contrast the recordings with the computer
generated audit trail.
- Accurate and complete copies. Calculate results from
raw data using a defined set of evaluation parameters (e.g., chromatographic
integrator events, calibration tables etc.). Save raw data, final results
and evaluation parameters on a storage device. Switch off the computer.
Switch it on again and perform the same tasks as before using data stored on
the storage device. Results should be the same as for the original
- Binding signatures with records. Sign a data file
electronically. Check the system design and verify that there is a clear
link between the electronic signature and the data file. For example, the
link should include the printed name or a clear reference to the person who
signed, the date and time and the meaning of the signature.
Accurate and Complete Copies - 11.10(b) and 11.10(c)
(b) "Procedures should be in place to o generate accurate
and complete copies of records in both human readable and electronic form
suitable for inspection, review, and copying by the agency. Persons should
contact the agency if there are any questions regarding the ability of the
agency to perform such review and copying of the electronic records"
Accurate and Ready Retrieval - 11.10(c)
(c) "Records must be protected to enable
their accurate and ready retrieval throughout the records retention
The agency wants to be able to trace final results back to
the raw data using the same tools as the user had when this data was generated.
This is probably one of the most difficult requirements to implement. Knowing
that in some instances the records must be kept for ten or more years, and as
computer hardware and software have a much shorter lifetime, one can anticipate
problems with this paragraph. While with the original interpretation of Part 11
this was required for each record and records had to be retained in their
original form for the full retention period as required by the predicate rule,
this has changed with the FDA’s new scope. Depending on a company’s business
practices, on the value of the record over time and based on justified and
documented risk assessment the new interpretation allows to copy the electronic
records to paper or to standard electronic formats such as PDF (Portable Data
Limited Access - 11.10(d)
"Procedures should be in place to limit system system
access to authorized users".
Limited access can be ensured through physical and/or
logical security mechanisms. Most companies already have procedures in place.
For logical security users typically log on to a system with a user I.D. and
password. Physical security through key locks or pass cards in addition to
logical security is recommended for high-risk areas, for example, for data
centers with network severs and back-data. These procedures should be very well
documented and validated.
User-Independent Computer Generated Time-Stamped Audit
Trails - 11.10(e)
"Procedures should be available to use 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. Record changes shall not obscure previously recorded
information. Such audit trail documentation shall be retained for a period at
least as long as that required for the subject electronic records and shall be
available for agency review and copying".
This paragraph has been the subject of many questions and
discussions. The problem lies mainly in how it is implemented, especially which
details are recorded. Most important is the word “independently”, which means
independently from the operator. The main purpose is to ensure and prove data
integrity. If the data has been changed the computer should record what has been
changed and who made the change. The audit trail functionality should be built
into the software and is especially important for critical computer related
processes with manual operator interaction.
Operational System Checks - 11.10(f)
"Procedures should be available to use
operational system checks to enforce permitted sequencing of steps
and events, as appropriate".
Use of Authority Checks - 11.10(g)
"Procedures should be available to use authority checks to
ensure that only authorized individuals can use the system, electronically sign
a record, access the operation or computer system input or output device, alter
a record, or perform the operation at hand".
Authority checks must be in place to ensure “authenticity,
integrity and confidentiality” of electronic records, and to ensure that the
signer cannot “readily repudiate the signed record as not genuine”. This
requires procedural and technical controls. Procedures should be in place to
assign access to systems and permitted tasks to individuals and the system
should be able to verify that an individual is permitted or authorized to
perform the requested function. Authority checks should be used when an
individual attempts to: access a system.
- Perform selected permitted tasks.
- Change a record.
- Electronically sign a record.
Use of Device Checks - 11.10(h)
"Procedures should be available to use device (e.g.,
terminal) checks to determine, as appropriate, the validity of the source of
data input or operational instruction".
This requirement refers to automatically determining the
identification and location of a piece of equipment hardware or another computer
system. An example would be that a computer system controlling an instrument
should automatically recognize the equipment as a valid input device through its
serial number. If the serial number is not set up in the computer’s database the
instrument cannot be used as an input device.
Device checks are not required in all cases but only
People Qualification - 11.10(i)
"Procedures should be available to determine that persons
who develop, maintain, or use electronic record/electronic signature systems
have the education, training, and experience to perform their assigned tasks".
People qualification is a GxP requirement and not specific
to Part 11. Procedures should be in place to document tasks and qualifications,
to develop a gap analysis and to develop an implementation plan on the gaps that
can be filled. This paragraph applies to users as well as developers of systems
and also to people supporting all kinds of computer systems including network
infrastructure. It also applies to part time employees as well as to 3rd
parties, for example, external service providers supporting an IT
Individual Accountability - 11.10(j)
"Procedures should be available to establish, and adhere
to, written policies that hold individuals accountable and responsible for
actions initiated under their electronic signatures, in order to deter record
and signature falsification".
Procedures should make employees aware that electronic
signatures have the same meaning as handwritten signatures. The content of the
procedures should be communicated in trainings and enforced. It is recommended
that employees should sign a statement like: “I understand that electronic
signatures are legally binding and have the same meaning as handwritten
Controls Over System Documentation - 11.10(k)
"Procedures should be in place for appropriate controls
over systems documentation including: (1) Adequate controls over the
distribution of, access to, and use of documentation for system operation and
maintenance. (2) Revision and change control procedures to maintain an audit
trail that documents time-sequenced development and modification of systems
System documentation includes all lifecycle documents from
validation planning, vendor assessment, development documentation and
specifications, to installation records, operation and test procedures and
protocols, change control and procedures to ensure system security and the
operator’s authenticity. All documentation should follow approved change control
processes and should be under revision control. Controls should be in place to
ensure that the most recent version of the document is always used.
Use of Digital Signatures for Open Systems -
"Persons who use open systems to create, modify, maintain,
or transmit electronic records shall employ procedures and controls designed to
ensure the authenticity, integrity, and, as appropriate, the confidentiality of
electronic records from the point of their creation to the point of their
receipt. Such procedures and controls shall include those identified for closed
systems, as appropriate, and additional measures such as document encryption and
use of appropriate digital signature standards to ensure, as necessary under the
circumstances, record authenticity, integrity, and confidentiality".
This requires software for document encryption and may
also require hardware and software for generating digital signatures. Typically
computer systems used in pharmaceutical operations are closed systems without a
need for digital signatures. An example for an open system would be if
analytical data generated by a contract laboratory is transmitted to the sponsor
through the public Internet. Examples on how open systems can be used are
described in Reference 5.
Requirements for Signed Electronic Records -
"(a) Signed electronic records shall contain
information associated with the signing that clearly indicates all
of the following:
(1) The printed name of the signer;
(2) The date and time when the signature was executed; and
(3) The meaning (such as review, approval, responsibility, or
authorship) associated with the signature.
(b) The items identified in paragraphs (a)(1), (a)(2), and (a)(3) of
this section shall be subject to the same controls as for electronic
records and shall be included as part of any human readable form of
the electronic record (such as electronic display or printout)."
Linking records to Signatures - 11.70
"Electronic signatures and handwritten
signatures executed to electronic records shall be linked to their
respective electronic records to ensure that the signatures cannot
be excised, copied, or otherwise transferred to falsify an
electronic record by ordinary means."
The main purpose of this requirement is to
link electronic signatures to relevant electronic records and also
to the signer of the records. The signer should be recognized by the
system through user I.D. and password and procedures and technical
controls should ensure that the signer is uniquely identified. This
definitely requires not only the development of procedures but even
more importantly behavioral changes on using I.D. codes and
passwords. The taboo against sharing a password with a colleague is
usually much lower than teaching somebody how to abuse a handwritten
signature. But under Part 11 both have the same consequence.
Software should also recognize any change to a signed record.
Typically this is done through linking the electronic signature to
the electronic audit trail.
General requirements for electronic
signatures - 11.100
"(a) Each electronic signature shall be unique
to one individual and shall not be reused by, or reassigned to,
(b) Before an organization establishes, assigns, certifies, or
otherwise sanctions an individual's electronic signature, or any
element of such electronic signature, the organization shall verify
the identity of the individual.
(c) Persons using electronic signatures shall, prior to or at the
time of such use, certify to the agency that the electronic
signatures in their system, used on or after August 20, 1997, are
intended to be the legally binding equivalent of traditional
(1) The certification shall be submitted in paper form and signed
with a traditional handwritten signature, to the Office of Regional
Operations (HFC-100), 5600 Fishers Lane, Rockville, MD 20857.
(2) Persons using electronic signatures shall, upon agency request,
provide additional certification or testimony that a specific
electronic signature is the legally binding equivalent of the
signer's handwritten signature."
Electronic signature components and controls
"(a) Electronic signatures that are not based
upon biometrics shall:
(1) Employ at least two distinct identification components such as
an identification code and password.
(i) When an individual executes a series of signings during a
single, continuous period of controlled system access, the first
signing shall be executed using all electronic signature components;
subsequent signings shall be executed using at least one electronic
signature component that is only executable by, and designed to be
used only by, the individual.
(ii) When an individual executes one or more signings not performed
during a single, continuous period of controlled system access, each
signing shall be executed using all of the electronic signature
(2) Be used only by their genuine owners; and
(3) Be administered and executed to ensure that attempted use of an
individual's electronic signature by anyone other than its genuine
owner requires collaboration of two or more individuals.
(b) Electronic signatures based upon biometrics shall be designed to
ensure that they cannot be used by anyone other than their genuine
Controls for identification codes/passwords -
Persons who use electronic signatures based
upon use of identification codes in combination with passwords shall
employ controls to ensure their security and integrity. Such
controls shall include:
(a) Maintaining the uniqueness of each combined identification code
and password, such that no two individuals have the same combination
of identification code and password.
(b) Ensuring that identification code and password issuances are
periodically checked, recalled, or revised (e.g., to cover such
events as password aging).
(c) Following loss management procedures to electronically
deauthorize lost, stolen, missing, or otherwise potentially
compromised tokens, cards, and other devices that bear or generate
identification code or password information, and to issue temporary
or permanent replacements using suitable, rigorous controls.
(d) Use of transaction safeguards to prevent unauthorized use of
passwords and/or identification codes, and to detect and report in
an immediate and urgent manner any attempts at their unauthorized
use to the system security unit, and, as appropriate, to
(e) Initial and periodic testing of devices, such as tokens or
cards, that bear or generate identification code or password
information to ensure that they function properly and have not been
altered in an unauthorized manner."
New Scope of 21 CFR Part 11
Although 21 CFR Part 11 has been in place for 10 years and
enforced started eight years ago, there is still confusion in the industry on
how to implement it. The regulation itself, earlier draft guidance documents and
early interpretations of FDA staff defined an electronic record as "Electronic
record means 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. Part 11
compliance was requested for all such records that have passed through 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 almost impractical. In some cases, companies even decided
against the use of new technology and stayed with paper because of the
anticipated additional complexity and cost involved with the implementation of
the technical control required by the rule. However, this was clearly not the
original intent and spirit of the rule which was issued to protect and further
public health while at the same time enabling the use of new technology!
With the release of the draft guidance on “Scope and
Applications for Part 11” in February 2003 (5) the FDA promoted a new and
narrower approach. With the final guidance released on September 3, 2003 and the
FDA’s announcement to re-examine Part 11 and initiate a new rule-making process,
this new approach became official and most probably will be the basis for an
updated regulation in the future.
The guidance states that Part 11 applies when:
- The record is required by a predicate rule, e.g.,
electronic batch records for 21 CFR Part 211 and electronic training records
in 21 CFR Part 58.
- The electronic records are used to demonstrate
compliance with a predicate rule, e.g., electronic training records for
compliance with 21 CFR Part 211.
Part 11 applies in one of the following situations:
- When electronic records are used instead of paper.
- When persons make printouts but still rely on the
electronic records in the computerized system to perform regulated
- Records submitted to the FDA, under predicate rules
(even if such records are not specifically identified in agency regulations)
in electronic format.
- Electronic signatures intended to be the equivalent
of handwritten signatures, initials and other general signings required by
While 1, 3 and 4 are obvious, 2 requires some
interpretation. It is related to hybrid systems where the computer is used to
generate, evaluate and/or transmit electronic records and the final results are
printed and the printout is maintained as the “master” record. The question is
if the electronic records existing on the computer system must comply with Part
FDA representatives interpreted this situation in various
presentations. The recommendations are illustrated in Figure 1. First we check
if the record is required by a predicate rule or used to demonstrate compliance
with a predicate rule. Next, we determine if the record fits in the new, narrow
scope. The main criterion is whether the record is maintained in electronic
format in place of paper format, or if the record is maintained in electronic
format in addition to paper records and if persons rely on the electronic record
to perform regulated activities. A “regulated activity” is any activity that is
required by a FDA regulation, for example, analytical test results are required
to be recorded by the FDA’s 21 CFR Part 211. In this case the regulated activity
is not limited to signing the record, for example, a paper printout of an
electronic record, but it also includes all steps from data acquisition and
evaluation. Finally, we make a risk assessment of the criticality of the Part 11
records and document the result. Based on the outcome appropriate Part 11
controls are implemented.
The last criterion is to evaluate the level of risk the
record has on product quality and data integrity. Examples of high-risks records
are electronic batch records and analytical records of final product testing.
Errors at this stage will not be identified and can no longer be recovered
before the product is shipped to the market. An example of a low-risk record
would be electronic planning documents such as cleaning or maintenance
schedules. Electronic standard operating procedures could fall into the medium
or low risk category, depending on what impact the procedure has on product
Figure 1: Steps to determine if records
are in the scope of part 11
The guidance makes a statement that the FDA will reexamine
Part 11 and exercise enforcement discretion for certain Part 11 requirements
until the new Part 11 is released: "While the re-examination of Part 11 is under
way, we intend to exercise enforcement discretion with respect to certain Part
11 requirements". Four other paragraphs are equally important:
- "That is, we do not intend to take enforcement action
to enforce compliance with the validation, audit trail, record retention,
and record copying requirements of Part 11 as explained in this guidance".
- "However, records must still be maintained or
submitted in accordance with the underlying predicate rules, and the Agency
can take regulatory action for noncompliance with such predicate rules".
- "Note that Part 11 remains in effect and that this
exercise of enforcement discretion applies only as identified in this
- "We will enforce all predicate rule requirements,
including predicate rule record and recordkeeping requirements".
While everybody seems to read and understand the first
part of #1 the words “as explained in this guidance” as well as the second,
third and fourth paragraph are frequently overlooked. For example, validation
and audit trail are requirements of many predicate rules and the FDA can always
take actions if they find deviations from predicate rules.
In the next few chapters we will take a closer look at the
The guidance states:
- "The Agency intends to exercise enforcement
discretion regarding specific Part 11 requirements for validation of
computerized systems (§ 11.10(a) and corresponding requirements in §
- "Although persons must still comply with all
applicable predicate rule requirements for validation (e.g., 21 CFR 820.70(i)),
this guidance should not be read to impose any additional requirements for
- "We suggest that your decision to validate
computerized systems, and the extent of the validation, take into account
the impact the systems have on your ability to meet predicate rule
- "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
- "For instance, validation would not be important for
a word processor used only to generate SOPs".
With #5 the guide gives an example on the meaning of
enforcement discretion. With the old interpretation there were lots of
discussions about Part 11 compliance of computer systems like word processing
systems. With this statement the FDA would not expect that such systems should
While in the example of word processing systems the
situation is quite obvious, in other examples it is not. The FDA expects a
justification based on a documented risk assessment (see #4 of above) for all
computer systems that are not validated or not fully tested.
Our recommendations are:
- Define risk categories for computer systems, for
example, high, medium or low.
- For each validation phase define the extent of
validation for each risk level. For example, vendor assessment for a
high-risk system may require a vendor audit and for medium and low risk
systems just documentation on the vendor’s reputation and experience.
- Assign each individual computer system used for GxP
applications to a specific risk level.
- Define validation steps for each individual system.
The four steps are very well described in a reference
paper “Risk-Based Validation of Commercial Off-the-Shelf Computer Systems” (7).
We recommend developing a procedure for consistent implementation. An example
SOP is shown in Reference 8.
The guidance states:
- "The Agency intends to exercise enforcement
discretion regarding specific Part 11 requirements related to
computer-generated, time-stamped audit trails (§ 11.10 (e), (k)(2) and any
corresponding requirement in §11.30)".
- "Persons must still comply with all applicable
predicate rule requirements related to documentation of, for example, date
(e.g., § 58.130(e)), time, or sequencing of events, as well as any
requirements for ensuring that changes to records do not obscure previous
- "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".
- "Audit trails can be particularly appropriate when
users are expected to create, modify, or delete regulated records during
Audit trail is a requirement of some FDA predicate rules,
for example 21 CFR Part 58 (GLP). Others don’t specifically mention audit trail
but require changes to data to be recorded, for example 21 CFR Part 211 (drug
cGMP) states in Paragraph 194b: "Complete records shall be maintained of any
modification of an established method employed in testing. Such records shall
include the reason for the modification and data to verify that the modification
produced results that are at least as accurate and reliable for the material
being tested as the established method". If the audit trail is not generated by
the computer it should be generated manually, as a minimum. A record’s integrity
is a basic requirement of regulations and users of computer systems must be able
to demonstrate this, especially for critical records.
#3 above mentions “other appropriate measures”. This means
you can use other techniques to demonstrate record integrity, for example to
demonstrate file integrity through hash values.
#4 is important as it talks about manual interaction with
the system. It is difficult to demonstrate record integrity if users sit in
front of a computer and can change data on the screen if there is no electronic
audit trail. This becomes really critical if a change of such data can have an
impact on critical records, for example, accuracy of product test results. In
this case the system should have a built-in electronic audit trail and the
function should be validated. This is one example where discretion would not be
exercised “as explained in this guidance”.
Copies of Records
The guidance states:
"We recommend that you supply copies of electronic records
- "Producing copies of records held in common portable
formats when records are maintained in these formats".
- "Using established automated conversion or export
methods, where available, to make copies in a more common format (examples
of such formats include, but are not limited to, PDF, XML, or SGML)".
- "In each case, we recommend that the copying process
used produces copies that preserve the content and meaning of the record".
- "If you have the ability to search, sort, or trend
Part 11 records, copies given to the Agency should provide the same
capability if it is reasonable and technically feasible".
- "You should allow inspection, review, and copying of
records in a human readable form at your site using your hardware and
following your established procedures and techniques for accessing records".
Copies of records is one of the most heatedly discussed
Part 11 requirements. During the generation, evaluation, transmission and
storage of electronic records different types of data are generated: original
digital data, sometimes also called raw data, meta data, intermediate results
and final results. Final results are either kept in electronic form, or they are
converted to paper or standard electronic files such as PDF or XML format.
In #1 and #2 the guide recommends different formats which
typically is quite easy to comply with. The more stringent requirement comes in
#3: preserve the content and meaning. Frequently it is not a problem to preserve
the content and meaning when converting original data. For example, when
converting a word document to a PDF file, most often the content and meaning is
preserved. You may loose some of the property information but this does not
change the meaning of the document. The situation looks different if you convert
graphics with a variety of different resolutions. With a PDF file you may not be
able to zoom into the details. If you need the highest resolution to demonstrate
compliance you may need the original software.
Sometimes the question comes up if a firm can keep the
original records and software for scientific reasons and make printouts for the
inspector. #4 and #5 make it very clear that the FDA wants to have the same
capabilities that the user has at the time of inspection, this means access to
the database and software for data sorting, searching and most likely
The guidance states:
"We recommend that you supply copies of electronic records
- "The Agency intends to exercise enforcement
discretion with regard to the Part 11 requirements for the protection of
records to enable their accurate and ready retrieval throughout the records
- "We suggest that your decision on how to maintain
records be based on predicate rule requirements and that you base your
decision on a justified and documented risk assessment and a determination
of the value of the records over time".
- "FDA does not intend to object if you decide to
archive required records in electronic format to nonelectronic media such as
microfilm, microfiche, and paper, or to a standard electronic file format
(examples of such formats include, but are not limited to, PDF, XML, or
- "Persons must still comply with all predicate rule
requirements, and the records themselves and any copies of the required
records should preserve their content and meaning".
- "As long as predicate rule requirements are fully
satisfied and the content and meaning of the records are preserved and
archived, you can delete the electronic version of the records".
The issues with record retention are somewhat similar as
with copying records. While the original interpretation of Part 11 required
maintaining the records in original form with reprocessability throughout the
entire retention period as required by the predicate rule, the new approach
allows other options. Most important is the statement that decisions about the
retention format should be based on the record’s value over time. The value of a
record is at its highest at the time when it is created, processed and displayed
or printed. The information is used to make decisions about a product release,
for example. If there is any doubt about correct processing the data can be
reprocessed either with the same or with different parameters, if this is
The value remains fairly high after the product is shipped
until it is fully accepted by the market, which means no complaints from
clients. The record quickly looses its value in the first years and the main
reason to retain it is to have it available for the next FDA inspection. In
research and development companies the value of the original record with
reprocessing capability remains high for a longer time for scientific reasons.
Such facilities want to be able to go back and look at the data again if new
scientific challenges come up.
The guide allows converting of the records into different
formats such as paper, microfiche or standard PDF files as long as the new
format can be used to preserve content and meaning and to demonstrate compliance
with the predicate rule. The main question is whether a paper printout or PDF
format has all the information to demonstrate compliance or if the original
record and software for reprocessing is required.
For hybrid systems the FDA inspector will normally ask for
the paper printout. If this includes all information original electronic records
are not required. However, in many situations they do not include all
information to preserve the content and meaning. An example is a computerized
analytical instrument, for example, a computerized liquid chromatograph with
spectral capability for peak purity and compound confirmation.
Figure 2 shows the records generated during and after an
analysis and all this information should be recorded either because it is
directly required by a predicate rule or to demonstrate compliance with a
predicate rule. While clients are primarily interested in the analysis results
with graphics showing the chromatogram and tables with sample amounts, the FDA
may want to see traceability of the final results back to instrument and method
parameters, instrument I.D., operator name, chromatographic parameters, peak
integration marks and calibration tables and audit trails for re-integration. As
it is inconvenient and very difficult to print all this information for each
analytical result it is recommended to keep it in original electronic form
together with the original software for reprocessing if the need arises.
2: Records in Chromatography
Problems arise when the original software is no longer
supported or can no longer be used for other reasons. In this case records can
be either migrated to work with updated or new software or can be converted to
other formats, such as paper. The time frame for this is typically not less than
3 to 5 years and the records have already lost much of their value for the
company and for the FDA.
Documentation of Part 11 Compliance
As explained in the previous paragraphs implementation of
some Part 11 controls should be based on a couple of criteria such as:
- Is the record required by predicate rule?
- Is a regulated activity dependent on the record?
- What is the company’s business practice?
- Have operators or supervisors access to data, can
they change data and can such data impact product quality?
If Part 11 controls are not implemented the FDA wants to
see a documented justification as to why not. Therefore each company is advised
to prepare such documentation. An example is shown in Figure 3 for a
computerized analytical system used in a pharmaceutical quality control
laboratory. The left upper part of the figure shows a graphical representation
of the system. The right upper part lists the business practices.
The sample is injected into a computer-controlled liquid
chromatograph. The signal is acquired by the PC (computer 1) and original data
are stored on the computer as digital data. Data are automatically processed on
this computer and results are transferred together with the evaluation
parameters to a second PC with a database (computer 2) for storage and printout.
The operator reviews the printout and depending on the findings may decide to
manually reevaluate the data. Finally the records are maintained in electronic
form because the company may need to reprocess the data later on for business
The left lower part of the figure shows a legend with
information on who has access to the data on which computer and what data can be
changed. In the right lower part of the figure we document the criticality of
the record, if the record is required by a predicate rule and if the regulated
activity depends on the record. In the middle lower part of the figure we
document our decisions and justifications.
Both computer systems must be validated according to the
high-risk categories. Computers 1 and 2 should have a built-in electronic audit
trail because operators have access to the records and operators can change
records, they are required by predicate rule and regulated activities depend on
the record. We also keep the records in electronic form in addition to the paper
printout because they may be needed to demonstrate compliance with the predicate
rule and the company may also maintain the records in electronic form for other
Figure 3: Documentation of Part 11
We frequently hear questions such as:
- Does this software have to comply with Part 11?
- I am using a system xy from vendor xz, do I have to
comply with Part 11?
- Our software does not have electronic audit trail,
can I still use it for GxP applications?
- Can I use the Internet on the same computer where I
run GxP applications?
- I print my GxP records right after acquisition
without operator interaction, does Part 11 apply?
- I am using Excel templates as a sophisticated
calculator. I don’t store records electronically. Does Part 11 apply?
Despite going through previous chapters of this primer,
the answers are not readily available for all questions. Questions like this can
only be answered when one has a good understanding of the application as well as
a good understanding of Part 11 principles. There are three sources for getting
· In this chapter we will discuss the most commonly used
Reference 11 includes an extensive list of questions and
Spreadsheet applications are popular in all kinds of
businesses. Results generated are frequently used to make business decisions.
They are also frequently used in regulated environments, for example, batch
releases in pharmaceutical manufacturing can be based on calculations by
spreadsheets. Spreadsheet programs were not designed for the regulated
environment and without preventive actions the risk that they will generate
errors is relatively high.
There are four possibilities to solve or reduce the
- Perform the tasks using other software that better
enable users to comply with regulations.
- Change the way spreadsheets are developed and used
and apply all functions built into the spreadsheet programs to increase the
level of compliance. Develop a gap analysis and a corrective action plan.
One action item can be step 3.
- Evaluate and implement “add on” software packages
that better enable users of spreadsheet programs to comply with regulations.
- Use data management software with built-in Excel
support and Part11/GxP functionality
While all four options are good alternatives we believe
that #2 has the most long-term benefits. It requires a good understanding of the
spirit of Part 11 and a good technical understanding of spreadsheet programs,
for example, Excel. Most important is to understand the functions to ensure
spreadsheet security and integrity.
We recommend the following steps:
- Develop, communicate and enforce a company policy and
master plan for spreadsheet calculations.
- Prepare an inventory list with all computers that run
- Standardize “development and use” as much as
- Protect spreadsheets using built-in standard software
and IT infrastructure (e.g., client/server).
- Validate spreadsheet calculations.
- Follow recommendations in Chapter 4 of this primer to
define and document other Part 11 controls and extent of implementation.
Document and justify your approach.
Labcompliance has developed a Macro & Spreadsheet quality
package (9). In this package each step is explained in detail. The package also
includes SOPs, templates and examples for easy implementation.
The package can be ordered from:
Figure 4 shows the result from an Excel application. The
Excel spreadsheet was optimized for highest data integrity, easy use and lowest
failures raters. This was achieved through:
- Limited and authorized access to the spreadsheet
through a secure server.
- The server directory is write-protected. Therefore
the spreadsheet cannot be changed and saved on the same directory.
- The source directory, file name and revision number
of the spreadsheet are printed together with the results. This demonstrates
that only the original spreadsheet has been used.
- Cells for data entry are in green. This makes it easy
for the user to only access cells for data entry.
- Cells that are not used for operators are protected
and cannot be used.
- Cells with results that are in specifications are in
green and cells with results that are out-of-specifications are in red.
- If there are out-of-specifications results operators
get hints on what steps to take for corrective actions.
- Data input are validated for plausibility. Operators
are alerted about input data that are outside allowed ranges. This reduces
errors during data entry.
- Results are displayed in table and graphics form.
- All menu items have been removed. Operators are only
able to start, print and exit.
- The entire spreadsheet is validated. The focus is
more on checking limited access, retrieval of correct files and correct
input and output locations than on verification of standard Excel
Figure 4: Result of an Excel
Scanning Paper to Electronic Files for Archiving and
Despite modern computer technology there are still many
paper records generated. Archiving large numbers of paper records requires large
storage capacities. Such paper archives are also more difficult to search than
electronic databases. Therefore companies prefer to scan paper records into
standard electronic files, such as PDF or XML and add meta data to facilitate
This procedure complies with Part 11 and other regulations
if specific controls are implemented. For example, 21 CFR Part 211.180 (d)
allows to retain either original records or true copies: "Records required under
this part may be retained either as original records or as true copies such as
photocopies, microfilm, microfiche, or other accurate reproductions of the
original records". Electronic standard files fall under the category “other
To ensure compliance with Part 11 and other regulations,
- Develop a procedure for the entire process.
- Validate the process to ensure “true copies”. This is
best done by scanning a document that requires the highest resolution. Scan
the document, print it and compare the printout with the original. Verify if
the resolution is within previously specified acceptance criteria.
- If an automated scanner is used, check if all pages
have been scanned.
- Convert the scan into a PDF file.
- Save the PDF file with a high security option. This
means users of the file can read but not change the file.
The Internet is increasingly used for all types of
businesses. This also includes the healthcare business. Two main applications
are the World Wide Web for all types of on-line transactions and e-mails for
exchanging messages without and with attachments. An example where the Internet
can be of significant advantage is shown in Figure 5. A pharmaceutical company
outsources part of its clinical studies or laboratory analyses to a contract
laboratory. The sample is sent through FedEx to the contract laboratory,
analyzed and the data sent back to the sponsor through e-mail with attached
Figure 5: Internet Application
Other examples for using the Intranet or Internet in the
healthcare business are:
- Release of batch approvals.
- · Approval and release of validation lifecycle
checkpoints and validation and reports.
- · Electronic artwork transfer.
- Remote approval of Certificates of Analysis at
- Updates, exchange and approval of training records
- Administration of electronic patient records.
- Billing information exchange between healthcare
provider and insurance.
- Tele Medicine (remote surgery, diagnostics, imaging).
- Drug prescription online.
- Electronic patient card.
- Centralized and local patient data administration.
When transporting a clinical study or any other data as
mentioned above, data traffic needs to adhere to:
- Confidentiality: The contents of the data should only
be accessible by authorized persons.
- Integrity: The data should be exactly the same at
source and destination computer.
- Authenticity: The authenticity of the sender of the
data must be guaranteed.
- Non-repudiation: Sender and recipient of the data
cannot deny to have sent or received the data.
The Internet by nature is an insecure and unreliable
environment and therefore without special precautions it is not compliant with
the requirements as mentioned above. However, when using the technical controls
that are available today combined with procedures the Internet can be as
“trustworthy” as paper systems. In this chapter we only give summary
recommendations, more details can be found in the Labcompliance primer: “Using
the Internet in Regulated Environments” (5).
1. Develop and enforce procedures for using the Internet.
They should include:
- ·Training programs for theory and use of modern
- Security procedures.
- Procedures to protect computers from viruses.
- Procedures for downloading data from the Internet.
2. Encrypt all information sent through the Internet.
3. Use a Virtual Private Network (VPN) for remote access.
4. Validate applications on the sending and receiving
5. Validate integrity of file transfer through checksum.
Program Logical Controller PLC
Program Logical Controllers (PLC) are used to control
equipment used in manufacturing. Data are either entered manually or downloaded
from a computer. Examples are temperature and pressure of an autoclave and valve
positions. If data are entered through local controllers and actual conditions
are printed through a local controller, such records are not in the scope of
Part 11. However, if parameters are loaded from a computer and actual conditions
are monitored and recorded through a computer with manual interaction through
operators, Part 11 applies.
Most computer applications used in FDA regulated
environments are probably supported by network infrastructure. In simple words
the network can be seen as a big pipe where data are pumped through. Most
important is to maintain trustworthiness of the data. There are a couple of
- Security: There are many connection points to the
network. Connection through one port gives access to the entire network if
there is no additional control to sections. Network security through
physical and/or logical controls is of utmost importance. Technical controls
should be validated and procedures enforced.
- Typically the network also supports high-risk
applications such as back-up and archiving of high-risk records. Such
applications should be validated and comply with Part 11.
- Loosing data or inaccurate file transfer is not only
a business problem but also violates the requirement for trustworthiness.
Therefore file transfer accuracy should be verified under normal and high
- Applications supported by the network should be
validated. Examples include Electronic Batch Records (EBR) Systems,
Enterprise Resource Planning (ERP) Systems and Laboratory Information
Management Systems (LIMS). The test environment should include the same
network components as the live environment.
- Network infrastructure should be qualified. This
mainly means good planning and documentation of the network through diagrams
and inventory lists. It also means using a well-controlled procedures for
In the following paragraphs the two steps for complete
network qualification and system validation are briefly described. They have
been extracted from Reference 10.
Steps to build a qualified network infrastructure:
- Specify network requirements.
Specifications should include: network devices, software, computer hardware,
computer peripherals and cables. Specifications are based on anticipated
current and future use of the network.
- Develop a network infrastructure plan.
- Design network infrastructure and drawings.
- Select equipment and vendors for computers, NOS,
network devices etc.
- Order equipment: computer hardware, software (OS,
NOS), network devices, peripherals.
- Install all hardware devices according to design
drawings and vendor documentation.
- Perform self-diagnostics, document hardware
installation and settings (this completes the IQ part).
- Document this as network baseline.
- Make a back-up of installed software and network
configurations. Whatever happens, it should be possible to return to this
- Test communication between networked computers and
peripherals and access control including remote access control.
- Develop and implement rigorous configuration
management and a change control procedure for all your network hardware and
software. This should also include updates of system drawings if there are
- Before applying any system changes to a production
environment they should be verified in a test environment to insure that
they do not impact the intended functionality of the system.
- Monitor ongoing network traffic using a network
health monitoring software.
Steps to validate a networked system:
- Develop a validation plan and schedule using your
validation master plan as a guideline.
- Specify application software that runs on the
qualified network e.g., networked data system.
- Select and qualify the vendor.
- Install application software and perform IQ set-up
(define and document configuration settings, verify “proper” software
installation through installation verification routines)
- Verify correct functioning of this application
software. Apply common computer validation practices for this.
- Testing should include network transactions under
normal and high load. For this test you can decide to refer to verifications
done as a built-in TCP/IP transfer protocol. The advantage is that this is
built into the system and done on an ongoing basis. However, this is not
100% accurate as there are rare situations where the test does not work. To
be on the safe side, you should use something like MD5 hash calculation
routines based on 128 bit strings. Ask the vendor of your application
software as sometimes such tests are built-in.
- Monitor ongoing performance of your application. The
type of performance test depends on the application.
- For networks supporting high-risk applications
monitor network connections and traffic using a network health monitoring
As part of the installation system drawings and diagrams
should be generated. They are an absolute must not only for setting up a network
and networked systems but even more importantly for maintaining them. They
should be part of the IQ documents and should include:
- Physical diagrams such as component locations and
- Logical diagrams like TCP/IP schemes and how
components interrelate with each other.
- If dynamic IP addressing is used in the network
scheme, a procedure should also be in place to indicate how this dynamic IP
addressing is being utilized (including the procedure for sub-masking of the
IP addresses). This will enable appropriate tracing of data or traffic flow,
in case such a tracing is needed to prove the data integrity and security.
Networks change frequently, so maintaining these diagrams
with documented version control is important. A good recommendation is to have
procedures in place for regular review of these diagrams, for example quarterly
Implementing the regulation on electronic signatures and
records will have major consequences. It is recommended to follow a step-by-step
- Form a task force with members from the IT
department, if existing, QA personnel and laboratory staff.
- Decide whether you intend to use electronic
signatures. Report the decision to the FDA, for example: “This is to certify
that "My Company" intends that all electronic signatures executed by our
employees, agents or representatives, located anywhere in the world, are the
legally binding equivalent of traditional handwritten signatures”.
- Create awareness for Part 11 among all employees,
especially on the accountability of electronic signatures. For example,
people should sign something like this: “I understand that electronic
signatures are legally binding and have the same meaning as handwritten
- Make an inventory of all computers in your
organization or department that generate records required by a predicate
rule or records that are used to demonstrate compliance with a predicate
- Develop a master plan and SOP for risk assessment.
- Determine the risk category for each system.
- Define a priority schedule to bring all computer
systems into Part 11 compliance.
- Develop a procedure on how to define Part 11
- Define Part 11 requirements for each system.
- Do a gap analysis to determine missing functionality
and procedures for systems in 7.
Develop an implementation plan to bring systems as identified in 7 into Part
- Estimate costs for the systems as identified in 7 and
for the whole project.
Develop procedures for limited system access to authorized individuals. This
should include a password policy.
- Develop procedures for implementing audit trails, to
ensure data integrity and for long-term archiving with data retrieval
throughout the entire retention period.
- Get management support and funding for the project.
- Code of Federal Regulations, Title 21, Food and
Drugs, Part 11 Electronic Records; Electronic Signatures; Final Rule;
Federal Register 62 (54), 13429-13466.
- L. Huber, “Validation of Computerized Analytical and
Networked Systems”, Interpharm Press, an IHS Health Group company,
Englewood, Colorado, USA, ISBN 1-57491-133-3, approx. 250 pages, 2002.
- GAMP 4 Guide: “Validation of Automated Systems”,
ISPE, Brussels, 2001 (order from www.ispe.org).
- Pharmaceutical Inspection Convention/ Pharmaceutical
Inspection Co-operation Scheme (PIC/S): “Good Practices for Computerized
Systems in Regulated GxP Environments”, 2003.
- Labcompliance, Internet Quality Package, 2005.
Order from www.labcompliance.com/books/internet.
- FDA Guidance for Industry Part 11, Electronic
Records; Electronic Signatures Scope and Applications (Draft February 2003,
Final version August 2003). Available at
- L. Huber, “Risk-Based Validation of Commercial
Off-the-Shelf Computer Systems”, Journal of Validation Technology, May 2005,
Vol 11, No. 3.
- Labcompliance Standard Operating Procedure; S-252.
“Risk-Based Validation of Computer Systems”. Order from
- Labcompliance, Macro & Spreadsheet Quality Package,
Order from www.labcompliance.com/books/macros.
- Labcompliance, Network Quality Package, 2005.
Order from www.labcompliance.com/books/network
- Labcompliance, “21 CFR Part 11: Electronic Records
and Signatures”, Frequently Asked Questions. Order from
Links to Other Websites
Recent FDA Inspection Findings Related to Part 11 and Computer
483's, Warning Letters, EIR's, Presentations: 2004-2007