PEER- RE VIE WED
A Historical View of 21 CFR Part 211.68
Orlando Lopez
The US Food and Drug Administrations 21 Code of
Federal Regulations (CFR) Part 211.2(b) was the origi-
nal section in the good manufacturing practice (GMP)
regulation containing the requirements applicable to
computer systems.
Section 211.2(b) was integrated in 1978 with 21
CFR 211.68, hereafter referred to as Section 211.68.
As in the earlier Section 211.2(b), Section 211.68
regulates computer systems performing operations
covered by the GMP regulation.
This paper reviews the progression of Section
211.68 since 1976, including the December 4, 2007
amendment. It examines the specific issues that
impact the computer system performing operations
covered by the GMP regulation and Section 211.68.
INTRODUCTION
The US good manufacturing practices guidelines for fin-
ished pharmaceuticals (GMPs) (1) were formally intro-
duced in 1963 (2) based upon the best practices of the
US Food and Drug Administration regulated activities.
In the 1970s, the GMP guidelines were significantly re-
vised, acknowledging the use of computer systems per-
forming operations covered by the GMP regulation (3).
The FDA 21 Code of Federal Regulations (CFR) Part
211.2(b) was the original section in the GMP regulation
containing the requirements applicable to computer
systems. Specifically, Section 211.2(b) put emphasis on
the following:
Computer backups
Documentation
Having hardcopy of master formulas
82 Journal of GXP Compliance
Specifications
Test records
Master production and control records
Batch production records (batch production and
control records)
Calculations.
Section 211.2(b) was integrated in 1978 with 21 CFR
211.68, hereafter referred to as Section 211.68. As in the
earlier Section 211.2(b), Section 211.68 regulates com-
puter systems performing operations covered by the
GMP regulation. It deals with computer systems vali-
dation and the controls to be exercised over computer
operation, data, and records.
Almost all FDA-regulated products are manufactured
under the control of computer systems. The manufac-
turing procedures, control, instructions, specifications,
and safety to be followed within such computer systems
are embodied in the application software (4) that drives
the computer. Depending on the complexity of the
software application, it may also contain information
required by the GMPs (e.g., master production record),
controlling data on product formulation, batch size,
yields, and automated in-process sampling and testing
procedures.
As computer technology and practices improved,
CFR 211.68 evolved as well. An amendment impact-
ing Section 211.68 was published in the Federal Register
(FR) that promotes the implementation of certain regu-
latory requirements in Section 211.68.
This article covers the progression of Section 211.68,
including the December 4, 2007 amendment. It exam-
ines the specific issues that impact the computer system
performing operations covered by the GMP regulations
and Section 211.68.

The maturity of the practices and technology im-
provements, coupled with the guidelines published by
FDA and industry groups, provide the main sources of
regulatory innovation and the gradual progression in
Section 211.68.
21 CFR SECTION 211.2(B)1976
On February 1976, the FR (5) published a proposed
rule to revise the pharmaceutical GMP regulations.
Section 211.2(b) was relevant for computer systems
and allowed the use of computer systems in the man-
ufacture, processing, packing, and holding of a drug
product.
Section 211.2(b) reads as follows:
(b) Use of computer in the manufacture, pro-
cessing, packing, and holding of a drug product is
also permitted. Appropriate controls shall be exer-
cised over computer operations to assure that only
authorized personnel institute changes in master
production and control records or other records.
A backup file of hard copy data entered into the
computer shall be maintained except where cer-
tain hard copy, such as calculations performed in
connection with laboratory analysis are eliminated
by computerization or other automated processes.
In such instances, a written record of the program
shall be maintained along with appropriate valida-
tion data. Hard data to be retained in case of acci-
dental erasure of the information stored in a com-
puter shall include:
Master formulas
Specifications
Test data
Other master production or control records
Batch production or control records, or programs
for calculations.
The 1976 original Section 211.68 contained require-
ments applicable to the calibration of scales, balances,
and other precision automatic, mechanical, and electronic
equipment. The highlights of Section 211.2(b) were:
Computer systems can be used to perform opera-
tions covered by the GMP regulation
There must be written procedural controls for
managing changes to infrastructure, application
software, and associated documentation
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There must be procedural controls and technolo-
gies to address and ensure the accuracy and secu-
rity of computer systems input and output (I/O) of
electronic records and data
Computer systems must have adequate controls to
prevent unauthorized access or changes to data,
inadvertent erasures, or loss.
FDAs timing in publishing Section 211.2(b) was
prudent. The regulated industry was rapidly mov-
ing into the computer age and there was a developing
need for GMP requirements applicable to computer
systems.
FINAL RULE1978
On September 29, 1978, FDA published 21 CFR Part
211.2(b) as a final rule. 21 CFR Part 211.2(b) was in-
tegrated with Section 211.68. The result of this integra-
tion was the updated Section 211.68, Automatic, Me-
chanical, and Electronic Equipment.
The complete 1978 Section 211.68 reads as follows (6):
(a) Automatic, mechanical, or electronic equip-
ment or other types of equipment, including com-
puters, or related systems that will perform a func-
tion satisfactorily, may be used in the manufacture,
processing, packing, and holding of a drug prod-
uct. If such equipment is so used, it shall be rou-
tinely calibrated, inspected, or checked according
to a written program designed to assure proper perfor-
mance. Written records of those calibration checks
and inspections shall be maintained.
(b) Appropriate controls shall be exercised over
computer or related systems to assure that changes
in master production and control records or other
records are instituted only by authorized personnel.
Input to and output from the computer or related
system of formulas or other records or data shall
be checked for accuracy. A backup file of data en-
tered into the computer or related system shall be
maintained except where certain data, such as cal-
culations performed in connection with laboratory
analysis, are eliminated by computerization or other
automated processes. In such instances a written re-
cord of the program shall be maintained along with
appropriate validation data. Hard copy or alterna-
tive systems, such as duplicates, tapes, or microfilm,
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designed to assure that backup data are exact and
complete and that it is secure from alteration, inad-
vertent erasures, or loss shall be maintained.
The importance of Section 211.68 is noted in the
following 2008 FDA warning letter issued to Merck &
Company (7). The observation states that the manufac-
turer failed to exercise appropriate controls over com-
puter or related systems to assure that changes in master
production are instituted and input and output from the
computer or related system of formulas are checked for
accuracy and maintained [21 CFR 211.68(b)], in that
there is no documentation to support software manu-
facturing change performed to the [redacted] used in
the manufacture of [redacted], lots [redacted] and [re-
dacted].
Section 211.68 contains the validation requirements
applicable to computer systems performing operations
covered by the GMP regulations. While not explicitly
stated, the phrase in Section 211.68(a) according to
a written program designed to assure proper perfor-
mance is generally taken to mean that written valida-
tion procedures and the associated maintenance proce-
dures are established.
All computer systems performing operations covered
by the GMP regulations require a written (8) validation
process.
Current practice defines computer systems validation
as Determination of the correctness of the final pro-
gram or software produced from a development project
with respect to the user needs and requirements. Vali-
dation is usually accomplished by verifying each stage
of the software development life cycle (9).
The 1978 version of Section 211.68 reveals the expec-
tations of FDA for computer systems performing opera-
tions covered by GMP regulations, as follows:
Security requirements to e-records, application
software, and system software
Computer systems must have adequate controls
to prevent unauthorized access or changes to
data, inadvertent erasures, or loss
There must be procedural controls and technolo-
gies to address and ensure the accuracy and
security of computer systems I/Os, electronic
records, and data.
Maintenance requirements
84 Journal of GXP Compliance
All appropriate controls must be exercised
over computer systems to assure that changes
in master production and control records or
other records are instituted only by authorized
persons
There must be written procedural controls
describing the maintenance of the computer sys-
tem, including an ongoing performance evalua-
tion and periodic reviews
Computer systems documentation and valida-
tion documentation shall be maintained
There must be written procedural controls for
managing changes to infrastructure and applica-
tion software, including documentation
Records control requirements
Computer systems electronic records must be
controlled including record backup, security,
and retention
Extent of type regulated computer systems
Computer and related systems.
Because the use of the word computer excluded data
processing systems that do not compute (10), the phrase
related systems was included in Section 211.68(b).
With the inclusion of the phrase computers and related
systems, FDA covers all computer systems that com-
pute and manage data (e.g., programmable logic con-
troller with SCADA application and server connectivity)
and those that control and monitor without computing,
transmitting, or storing data (e.g., stand alone program-
mable logic controller).
The implications of the word validation created
misunderstanding to those who work in the FDA-
regulated industry and are knowledgeable in software
engineering. In the software engineering context, the
word validation means a one-time occurring planned
test. By 1978, the FDA expectation was to keep com-
puter systems performing operations covered by GMP
regulations under total quality management. This total
quality management concept was embraced in the late
1990s (11) by the FDA-regulated industry.
Another requirement covered in the GMP regulation
applicable to automated operations is the verification
by a second individual of manufacturing process. Par-
ticularly, these requirements addressed yield calcula-
tion (211.103), adding materials to the batch (211.101

(c) and (d), verifying equipment cleaning (211.182), and
checking the sequence of batch production and control
records (211.188(b)[11].
The intent of the verification by a second individual
of the applicable manufacturing processes is to assure
that each significant step during the manufacturing
process is performed properly and that the verification
is recorded.
If a computer system performs a manufacturing pro-
cess that requires verification by a second individual, it
may not be necessary to explicitly record the verifica-
tion made on each of a series of automated steps. The
preamble of the 1978 amendment, in the paragraph
282, states that the requirement in Section 211.101(c) is
met if the second individual verifies that the automated
system is working properly.
COMPLIANCE POLICY GUIDES1982
In 1982, the issue of double check was re-visited, and
FDA published two significant compliance policy guides
(CPGs) (12, 13) to supplement Sections 211.188(b)[11]
and 211.68 of the regulations.
FDA published CPG 425.500 (formerly 7132a.08),
Identification of Persons on Batch Production and Con-
trol Records specifically to address Section 21 CFR
211.188(b)[11]. Complying with CPG 425.500 consists
of conforming to the following:
Documentation that the application software con-
trolling the execution of the automated process
contains adequate checks, and documentation of
the performance of the application software itself.
Validation of the performance of the computer
application software controlling the execution of
the automated process. Conforming to the valida-
tion of the performance of the computer applica-
tion software is significant. The required double
check can be replaced by an automated single
check if it demonstrably provides at least as much
assurance of correctness.
Recording specific checks in batch production and
control records of the initial step, any branching
steps and the final step.
The second CPG, published by FDA in 1982,
complemented the I/O checks referenced in Sec-
tion 211.68. According to CPG 425.400 (formerly
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7132a.07), I/O Checking, computer I/Os are to be test-
ed for data accuracy as part of the computer system
qualification and, after the qualification, as part of the
computer systems on-going performance evaluation
procedure.
CPG 425.400 is based on the realistic anticipation
that computer system I/O errors can occur on validated
systems. A computer component (e.g., logic circuits,
memory, microprocessor) or device (e.g., modems, dis-
plays) can fail after it has been tested. Another source of
computer system I/O malfunctions are electromagnetic
interference (e.g., radio-frequency interference, electro-
static discharge, and power disturbance). Software er-
rors, undetected during the validation process, may also
be the source of I/O errors. The verification of outputs
also ensures that each reproduced document uses as
input(s) reliable and accurate data.
In order to detect errors before a computer system
makes decisions using tainted data, an on-going perfor-
mance evaluation process shall be established (14) and
followed to verify hardware and software I/Os during
the operation of the system.
FORMAL GUIDELINE1983
FDA published the formal guideline Guide to Inspection
of Computerized Systems in Drug Processing in 1983 (15).
This guideline stressed software validation, infrastruc-
ture qualification, and operations support. Operations
support includes backups, I/O checks, process and
computer systems documentation, monitoring of com-
puter operations, alarms, and system recovery.
This guide provides recommendations regarding
Section 211.68 on the following issues:
Computer systems may be used on operations
covered by the pharmaceutical GMP regulation.
Such computer systems require calibration proce-
dural controls.
Computer systems and infrastructure may need a
periodic calibration in certain parts of the equip-
ment or the control system. One example is in
infrastructure, where calibrated sensors are dedi-
cated to intrusion detections.
Implementation of software security procedural
controls and technologies to ensure that only
authorized personnel can make changes to master
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production, control, or other computer records
and files.
Section 211.68(b) also requires appropriate con-
trols over application and network components
to ensure that only authorized personnel make
changes in master, production, and control, or
other records.
Access to electronic records should be restricted
and monitored throughout the systems software
with its required logon, security procedures, and
audit trail. If the data are transmitted over com-
munication networks similar to the Internet, the
network shall employ electronic-based solutions to
ensure secure information, authenticity, informa-
tion integrity, and proof of sender and receiver, as
applicable, from the point of their creation to the
point of their receipt.
I/O checks procedural controls and technologies
must be implemented for the accuracy and secu-
rity of computer systems inputs, outputs, and data.
The objective of the I/O checks is to develop a
method to prevent inaccurate data inputs and
outputs. I/Os in, at least, critical process param-
eters should be monitored to ensure the process
remains within the established parameters. When
monitoring data on quality characteristics dem-
onstrates negative tendencies, the cause should be
investigated, corrective action may be taken, and
revalidation considered.
As an example of how FDA enforces the I/O
checks, a drug manufacturer was cited (16) for fail-
ing to assure that input and output for a computer
had been checked for accuracy from the Total
Chrom Data Acquisition System, which is used to
run your firms HPLC instruments during analysis
of drug products. For example, electronic data
files were not routinely checked for accuracy and,
as mentioned in the above observations, our inves-
tigators found numerous discrepancies between
the electronic data files and documentation in
laboratory notebooks.
The use of inputs edits (17) to mitigate the need
for extensive I/O checks. Edits can also be used
to make up information and give the errone-
ous impression that a process is under control.
86 Journal of GXP Compliance
These error overrides must be documented
during the design.
Implementation of acceptable error handling
procedures including documentation, error veri-
fication, correction verification, and allowed error
overrides including documentation of overrides.
Effective maintenance of accurate backup files of
input data, which must be secure from alteration,
loss, or inadvertent erasure. In summary, e-records
must be secure and controlled.
REVISED 211.681995
Section 211.68 was revised in early 1995 as part of the
final rule for the GMP regulations (18). The objective
of this amendment was to make clear the extent and
frequency of scrutiny necessary to verify the accuracy of
the computer systems and related systems I/O checks.
According to this revision, a process must be developed
to prevent erroneous data inputs and outputs. The pro-
cess to prevent erroneous I/Os is left up to the manufac-
turers discretion. The extent and frequency of the I/O
checks must be guided by a written procedural control
and based upon a variety of factors such as the complex-
ity and consistency of the computer systems. This was
the beginning of a risk-based approach.
The updated Section 211.68(b) reads as follows. The
sentence in italic represents the section that was up-
dated.
(b) Appropriate controls shall be exercised over
computer or related systems to assure that changes
in master production and control records or other
records are instituted only by authorized person-
nel. Input to and output from the computer or relat-
ed system of formulas or other records or data shall
be checked for accuracy. The degree and frequency
of input/output verification shall be based on the com-
plexity and reliability of the computer or related system.
A backup file of data entered into the computer or
related system shall be maintained except where
certain data, such as calculations performed in
connection with laboratory analysis, are eliminated
by computerization or other automated processes.
In such instances a written record of the program
shall be maintained along with appropriate valida-
tion data. Hard copy or alternative systems, such as

duplicates, tapes, or microfilm, designed to assure
that backup data are exact and complete and that
it is secure from alteration, inadvertent erasures, or
loss shall be maintained.
I/Os to GMP control systems are put to the test dur-
ing the qualification phase typically after the installation
of field devices or instrumentation. For example, the
field wiring/half-loop checks consist of the connection
qualification between the field devices and I/O modules
of the control system. The qualification may also in-
clude connections to other control or computer systems
and testing the connections within the primary system.
During the on-going performance evaluation, the I/O
verifications may consist of implementing the similar
tests carried out during the qualification phase.
DRAFT AMENDMENT1996
In 1996, a draft amendment (19) to the GMP regula-
tions was issued. It incorporated specific requirements
applicable to the validation of computer systems. The
1976 Section 211.2(b) and the 1978 Section 211.68(b)
of the respective GMP regulation established that com-
puter systems documentation should be maintained. In
particular, both sections required that a written record
of the application software shall be maintained along
with appropriate validation data. It was suggested that
the phrase appropriate validation data be replaced by
data establishing proper performance. The updated
Section 211.68(b) reads as follows; the words in italic
represent the revised section:
(b) Appropriate controls shall be exercised over
computer or related systems to assure those chang-
es in master production and control records or
other records are instituted only by authorized per-
sonnel. Input to and output from the computer or
related system of formulas or other records or data
shall be checked for accuracy. The degree and fre-
quency of input/output verification shall be based
on the complexity and reliability of the computer
or related system. A backup file of data entered into
the computer or related system shall be maintained
except where certain data, such as calculations per-
formed in connection with laboratory analysis, are
eliminated by computerization or other automated
processes. In such instances a written record of the
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program shall be maintained along with data estab-
lishing proper performance. Hard copy or alternative
systems, such as duplicates, tapes, or microfilm,
designed to assure that backup data are exact and
complete and that it is secure from alteration, inad-
vertent erasures, or loss shall be maintained.
According to the proposed amendment, the key con-
cept is that the drug manufacturer shall establish the
intended use of the computer system. This change is
proposed to emphasize that the drug manufacturer
must actually establish proper performance.
The phrase proper performance relates to the gen-
eral principle of validation (20). Planned and expected
performance is based upon predetermined design spec-
ifications and, consequently, intended use.
It is essential to establish the intended use of a com-
puter system in the beginning of a computer systems
lifecycle. The lifecycle starts when the computer system
is recommended; goes through the development, use,
and maintenance of the system; and does not end until
the system retires. As part of the development activi-
ties, a computer system is designed and implemented,
followed by a rigorous qualification testing process. All
of these steps are documented with design reviews and
approvals.
The system lifecycle process was well known by the
software engineering community in the 1960s, but was
not adopted by the FDA-regulated industry until the
late 1990s (11).
The computer systems lifecycle process fulfills FDAs
approach to quality by design (QbD). QbD should be a
key element of any quality system. It ensures that qual-
ity is designed and built into the computer system devel-
opment and maintenance.
As part of the 1996 proposed rule, QbD was add-
ed to the GMP as well a Subpart L, 211.220. Section
211.220(a) required validation of all manufacturing pro-
cesses, including the computer systems controlling or
monitoring the manufacturing process.
The draft amendment was never implemented (refer
to the proposed rule; withdrawal [21, 22]). The intend-
ed use requirement was not incorporated in Section
211.68(b). Many FDA drug regulation-related guideline
documents refer to the intended use. This is now a
current practice, not in the GMP regulation.
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FINAL 21 CFR PART 111997
In March of 1997, FDA issued the final Title 21 of the
Code of Federal Regulations; Electronic Records, Elec-
tronic Signatures (hereafter referred to as Part 11) (23).
Part 11 was published in 1997 after the industry re-
quested, in the late 1980s, FDA guidelines for compli-
ance use of electronic signatures. Part 11 defines the
environment under which paperless batch records can
be used. In addition to the regulation on electronic sig-
natures published in 1997, the electronic records of Part
11, Subpart B, reconcile Section 211.68 and other GMP
regulations on computer systems.
The Table shows a brief comparison of the similar sec-
tions concerning Section 211.68 and Subpart B in Part
11. In the context of the Table, Section 211.68 covers the
high level requirements associated with computer sys-
tems. Part 11 enhances Section 211.68 by providing ad-
ditional requirements associated with computer systems
performing operations covered by drug GMP regulations.
One requirement covered in Part 11 is intended use.
Corresponding to Section 11.10(a), the validation of
computer systems is required to ensure accuracy, reli-
ability, consistent intended performance, and the ability
to discern invalid or altered records.
Audit trails are an interesting requirement in Part
11. Section 11.10(e) requires controls and procedures
to include the 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....
FDA exercises enforcement discretion related to
computer-generated, time-stamped audit trails (Section
11.10(k)(2) and any corresponding requirement in Sec-
tion 11.30). However, computer systems applications
performing operations covered by GMP regulations
must comply with all GMP-related predicate regulations
(24) associated with documentation. Examples of such
predicate rule requirements are date, time, or sequenc-
ing of events, as well as any requirements for ensuring
that changes to records do not obscure previous entries.
From time to time, observations related to audit trails
by FDA have been noted. A warning letter issued to To-
mita Pharmaceutical in 2008 (25) pointed out that the
company had lacked secure audit trails to protect data
stored on the computer system.
88 Journal of GXP Compliance
Because of the widespread use of computer systems
performing operations covered by the GMP regulations,
the author of this article believes future versions of Sec-
tion 211.68 will include an explicit requirement for au-
dit trails.
As stated back in 2001 (26), the reader may conclude
that Subpart B in Part 11 is not essential to delineate
the FDA regulatory requirements on computer systems
performing operations covered by the GMP regulations.
Future versions of Section 211.68 may include ele-
ments of the electronic records of the current 21 CFR
Part 11. At that time, Subpart B may be removed from
Part 11.
Part 11 is beyond the scope of this discussion. Several
publications have been written about the requirements
in Part 11 and how to comply with these requirements.
AMENDMENT TO SECTION 211.682008
In September 2008, FDA issued an amendment to the
Final Rule (27) that impacted Section 211.68. Since
1978, FDA has not significantly updated the GMP regu-
lation. This 2008 amendment is a result of FDAs intent
to amend the GMP regulation published in the CFR
(28, 29, 30) and again addresses the issue of the double
check when a manufacturing operation is performed
by automated equipment rather than by an individual.
This amendment relates to CPG 425.500, Identification
of Persons on Batch Production and Control Records.
FDA states that certain operations (i.e., automated
equipment use as described in Section 211.68) may be
performed by automated equipment and verified by a
person, rather than one person performing an opera-
tion and another person verifying that the operation
was correctly performed. This amendment eliminates
the double check for critical steps in Sections 211.101(c),
211.103, 211.182, and 211.188(b)(11) if an automated
system is used.
Section 211.68(c), which was added to Section
211.68, reads as follows:
(c) Such automated equipment used for perfor-
mance of operations addressed by Sec. 211.101(c)
or (d), 211.103, 211.182, or 211.188(b)(11) can sat-
isfy the requirements included in those sections
relating to the performance of an operation by one
person and checking by another person if such
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TABLE: Comparison of 21 CFR 211.68 and 21 CFR Part 11.

211.68 21 CFR Part 11
Computer systems can be used to perform operations covered by the GMP regulation. 11.10(a)
These computer systems require a validation program.
Computer systems documentation and validation documentation shall be maintained. 11.10(k)
There must be a system to control changes to the computer hardware and software, 11.10(c); 11.10(d); 11.10(e); 11.10(f);
including documentation. 11.10(g); 11.10(h)
Computer systems electronic records must be controlled including records retention, 11.10(c); 11.10(d); 11.10(e); 11.10(g);
backup, and security. 11.10(h)
Based on the complexity and reliability of computer systems there must be procedural 11.10(a); 11.10(b); 11.10(c); 11.10(d);
controls and technologies to ensure the accuracy and security of computer systems I/Os 11.10(e); 11.10(f); 11.10(g); 11.10(h);
electronic records and data. 11.10(k)
Computer systems must have adequate controls to prevent unauthorized access or 11.10(c); 11.10(d); 11.10(e); 11.10(g);
changes to data, inadvertent erasures, or loss. 11.10(h)
Computer electronic records must be controlled, and this includes record backup, secu- 11.10(c); 11.10(k)
rity, and retention.
There must be a written program detailing the maintenance of the computer system, 11.10(k)
including an on-going performance evaluation and periodic reviews.
Specifically for Sections 211.101(c), 211.103, 211.182, and 211.188(b)(11), verification 11.10(a); 11.10(f)
by a second individual may not be necessary when automated equipment is used as
described under Section 211.68.

equipment is used in conformity with this section,
and one person checks that the equipment prop-
erly performed the operation.
In addition to the changes in 211.68, the following
sections were changed:
Section 211.101(c) and 211.101(d)charge-in of
components and containers
Section 211.103calculation of yields
Section 211.182equipment cleaning and
maintenance
Section 211.188(b)[11]batch production and
control records.
Similar to 211.101(d), the typical addition to these
sections is the statement: Each component shall either
be added to the batch by one person and verified by a
second person or, if the components are added by automat-
ed equipment under Sec. 211.68, only verified by one person.
Industry Comments
Many of the industry comments in reaction to the pro-
posed GMP rule expressed opposition to the provision
regarding verification by a second individual. These and
other comments can be found on the Internet (31). In this
authors opinion, some of the most relevant comments or
recommendations against Section 211.68(c) in the docket
are as follows.
One comment to the amendment read: If the process
control system used to perform the initial activity is auto-
mated and has been adequately validated in accordance
with current FDA and industry guidance, does the output
of that process still need to be checked for accuracy by a
human being?
The response to this inquiry is found in the pre-amble
under Comment 19. FDA is linking the verification of the
accuracy of the computer systems with the I/O require-
ments in 211.68(b) and the CPG 425.400, I/O Checking.
Related to the impact of regulated products safety and
efficacy by the computer systems, FDA identifies one area
to perform risk assessments. According to the FDA re-
sponse to Comment 19, the current thinking is that I/
Os must be one area of relevance. Although increas-
ingly sophisticated controls and safeguards have been

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implemented for some automated systems, our policy has
been that some degree of human oversight, supervision,
verification, monitoring, or checking is still necessary to
verify proper performance as part of assuring the identity,
strength, quality, and purity of drug products.
Another industry comment read: The proposed
changes still require the involvement of at least one per-
son in each of these circumstances and prevent the use of
a controlled system or systems which both perform and
independently verify the relevant operations.
FDA addressed this comment (Comment 25) by stat-
ing that the agency rejects the comment. Consistent with
the response by FDA to Comment 19, FDA believes that
human verification of certain processing steps, even when
those steps are performed by automated equipment, is still
necessary.
Many industry comments also recommended the
extension of Section 211.68(c) as it relates to automated
laboratory equipment as in Section 211.194(a)(8). The rec-
ommendation to extend Section 211.68(c) to 211.194(a)(8)
and other similar sections in the GMP was declined. In
response to Comment 23, FDA states:
when automated equipment is used to perform
a laboratory test, typically a person initiates the test
and ensures that the correct equipment is used and
that it operates properly. In this situation, one person
assists in or oversees the performance of the labora-
tory test and a second person reviews the records for
accuracy, completeness, and compliance with es-
tablished standards. Thus, the use of equipment to
perform laboratory tests, though permissible, is not a
situation in which automated equipment (rather than
a person) performs an operation and a person verifies
that performance, which is the situation addressed in
revised Sec. 211.68(c).
FDA lost a great opportunity to incorporate to the
amendment the intended use requirement discussed
elsewhere in this paper. Similar regulation is found in the
Quality System section applicable to medical devices (refer
to Section 820.70(i)).
CGMP REGULATION2008
In the 2008 current good manufacturing practices
(CGMPs) regulation, effective December 4, 2008, the fol-
lowing are the applicable regulations to computer systems:
90 Journal of GXP Compliance
Computer systems can be used to perform opera-
tions covered by the GMP regulation. These com-
puter systems require a written validation process.
Computers systems documentation and validation
documentation shall be maintained.
There must be procedural controls for managing
changes to infrastructure and application software,
including documentation.
Computer systems electronic records must be con-
trolled including records retention, backup, and
security.
Based on the complexity and reliability of computer
systems there must be procedural controls and
technologies to ensure the accuracy and security
of computer systems I/Os electronic records and
data.
Computer systems must have adequate controls to
prevent unauthorized access or changes to data,
inadvertent erasures, or loss.
There must be written procedural controls describing
the maintenance of the computer system, including an
on-going performance evaluation and periodic reviews.
Specifically for Sections 211.101(c), 211.103, 211.182,
and 211.188(b)(11), verification by a second individual
may not be necessary when automated equipment is
used as described under Section 211.68.
The italicized statements depict the difference be-
tween the 1976 regulation and 2008 regulation.
SUMMARY
Since 1970, FDAs attention to the computer systems
performing operations covered by the drug GMP regu-
lation has increased due to the increase in FDA-regulat-
ed products being manufactured under the control of
computer systems directly impacting drug quality.
By 1978, FDA published a comprehensive regula-
tion on how GMP applies to computer systems. Section
211.68 introduces in general the total quality manage-
ment of computer systems. In particular, Section 211.68
requires security on e-records, application software, and
system software; maintenance procedural controls to
computer systems; and e-records controls. These three
critical requirements provide the high degree of assur-
ance of the reliability, consistency, and accuracy of com-

puter systems performing function defined by the GMP
regulation.
The early 2000s have seen an increase in the use of
more sophisticated software-driven on-line control sys-
tems to collect and manage records that demonstrate
regulated products safety and efficacy. As these soft-
ware-driven control systems have become more compli-
cated, the need for up-to-date regulations to document
and demonstrate that these systems operate properly
has become more important.
Industry practices have moved to a risk-based ap-
proach, which includes the complexity and reliability of
such systems. One area to stress during the risk assess-
ment to computer systems is the I/Os.
Technology improvements and the guidelines pub-
lished by FDA and industry groups provide the main
source of regulatory innovation and the gradual pro-
gression of Section 211.68.
Section 211.68 has a lot of possibilities for future
growth. For example, the author of this article considers
that in the future we may see elements of the current
Part 11 in Section 211.68. At that time, Subpart B may
be removed from Part 11.
REFERENCES
1. FDA, 21 Code of Federal Regulations, Part 210-211 (Current
Good Manufacturing Practice), FDA, Rockville, MD.
2. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Part 133 Drugs; Current Manufacturing Practice in Manufac-
turing, Processing, Packing, or Holding, 28 Federal Register
1459, 6385-6387, June 20, 1963.
3. In the context of this article, the statement operations covered
by the drugs GMP regulation means that those operations
are the process/business operations carried out on a product
covered in the GMPs. It is any computer system used in the
manufacture, processing, packing, or holding of pharmaceu-
ticals, and which impact the safety, identity, strength, quality,
and purity of such products.
4. Application software consist of programs written to specify
user requirements for the purpose of performing a designated
task such as process control, laboratory analyses, and acquisi-
tion/processing/storage of information required by the GMP
regulation.
5. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Proposed Rule; Current Good Manufactur-
Orlando Lopez
ing Practice in Manufacture, Processing, Packing, or Holding,
Federal Register, Vol. 41 No. 31, 6878-6891, February 13, 1976.
6. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Final Rule; Current Good Manufacturing
Practice in Manufacture, Processing, Packing, or Holding,
Federal Register, Vol. 190 No. 31, 45014-45087, September 29,
1978.
7. FDA, Warning Letter to Merck & Company, Inspections,
Compliance, Enforcement, and Criminal Investigations, FDA.
gov, April 28, 2008.
http://www.fda.gov/ICECI/EnforcementActions/WarningLet-
ters/2008/ucm1048323.htm
8. In the context of records the term written means recorded, or
documented on media, paper, electronic or other substrate.
9. National Bureau of Standards Special Publication, Validation,
Verification, and Testing of Computer Software, 1981.
10. FDA, comments paragraph 189, 43 FR 45042, Sept 29, 1978.
11. Grigonis, G. J., Subak, E. J., Wyrick M. L., Validation Key
Practices for Computer Systems Used in Regulated Operations,
Pharmaceutical Technology, June 1997.
12. CPGs associated to computer-related systems were issued by
FDA throughout the 1980s as guidelines or interpretations
of the applicable CFRs. The CPGs associated with computer
systems can be found in the Compliance Policy Guides Manual,
Chapter 4, Human Drugs, Sub Chapter 425, Computerized
Drug Processing, 06-20-2006.
13. Lpez, O., A Guide to Computer Compliance Guides, Journal
of cGMP Compliance, January 1997.
14. The medical device Quality System regulation (21 CFR
820.3(k)) defines establish to mean, define, document, and
implement. Where it appears in this paper, the words estab-
lish and established should be interpreted to have this same
meaning.
15. FDA, Guide to Inspection of Computerized Systems in Drug
Processing, Food and Drug Administration, Center for Drug
Evaluation and Research, Rockville, MD, 1983.
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Compliance, Enforcement, and Criminal Investigations, FDA.
gov, February 1, 2007, http://www.fda.gov/ICECI/Enforcemen-
tActions/WarningLetters/2007/ucm076260.htm.
17. Editssoftware may be written in such a manner as to reject
or alter certain input or output information, which does not
conform to some pre-determined criterion or otherwise fall
within certain pre-established limits. Edits can be a useful way
of minimizing errors and/or to reject erroneous entries. Edits
Spring 2011 Volume 15 Number 2 91
PEER-RE VIEWED
can also be used to falsify information and give the erroneous
impression that a process is under control.
18. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Final Rule; Current Good Manufacturing
Practice in Manufacture, Processing, Packing, or Holding of
Drugs; Amendment of Certain Requirements for Finished
Pharmaceuticals, Federal Register, Vol 60 No. 13, 4087-4091,
January 20, 1995.
19. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Proposed Rule; Current Good Manufactur-
ing Practice; Proposed Amendment of Certain Requirements
for Finished Pharmaceuticals, Federal Register Vol 61 No. 87,
20104-20114, May 3, 1996.
20. Center for Drug Evaluation and Research, Center for Biologics
Evaluation and Research, and Center for Veterinary Medicine
(CVM) Food and Drugs Administration, Guidance for Industry
Process Validation: General Principles and Practices, FDA, Rock-
ville, MD, January 2011.
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Parts 210 and 211, Direct Final Rule; Amendment to the Cur-
rent Good Manufacturing Practice Regulations for Finished
Pharmaceuticals; Federal Register, Vol. 72 No. 283, 68064-
68070, December 4, 2007.
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Parts 210 and 211, Proposed Rule; Amendment to the Current
Good Manufacturing Practice Regulations for Finished Phar-
maceuticals; Companion Document to the Direct Final Rule;
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2007.
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Part 11, Final Rule; Electronic Records; Electronic Signatures,
Federal Register Vol. 62 No. 54, 13429-13466, March 20, 1997.
24. Predicate regulationsFederal Food, Drug, and Cosmetic Act,
the Public Health Service Act or any FDA Regulation, with the
exception of 21 CFR Part 11. Predicate regulations address the
research, production, and control of FDA regulated products.
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Inspections, Compliance, Enforcement, and Criminal Investi-
gations, FDA.gov, January 14, 2008, http://www.fda.gov/ICECI/
EnforcementActions/WarningLetters/2008/ucm1048433.htm.
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Manufacturing 13 Years Later, Pharmaceutical Engineering,
May/June 2001.
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Parts 210 and 211, Final Rule; Amendments to the Current
92 Journal of GXP Compliance
Good Manufacturing Practice regulations for Finished Phar-
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September 8, 2008.
28. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Amendments to the Current Good Manu-
facturing Practice Regulations for Finished Pharmaceuticals;
Companion Document to the Direct Final Rule, Federal Register,
Vol. 72, No. 232, 68113-68116, December 4, 2007.
29. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Current Good Manufacturing Practice;
Amendment of Certain Requirements for Finished Pharmaceu-
ticals; Withdrawal, Federal Register, Vol. 72 No. 232, 68111-
68113, December 4, 2007.
30. FDA, Code of Federal Regulations, Title 21 Food and Drugs,
Parts 210 and 211, Direct Final Rule; Withdrawal; Amendment
to the Current Good Manufacturing Practice Regulations for
Finished Pharmaceuticals; Withdrawal, Federal Register, Vol. 73
No. 66, 18440-18441, April 4, 2008.
31. The industry comments to the Section 211.68 amendment can
be found at http://www.regulations.gov/fdmspublic/compo-
nent/main?main=DocketDetail&d=FDA-2007-0614, accessed
March 1, 2011. GXP
ACKNOWLEDGMENT
The author would like to express his gratitude to Siri H.
Segals for contributions to this article.
ARTICLE ACRONYM LISTING
CFR Code of Federal Regulations
FDA US Food and Drug Administration
FR Federal Register
GMP Good Manufacturing Practice
I/O Input/Output
ABOUT THE AUTHOR
Orlando Lopez is the practice leader at US Data Management, LLC,
with more than 25 years of software quality assurance experience
and more than 28 years in QA and compliance in the FDA-regulat-
ed environment. His special interest is the GMP compliance issues
applicable to computer systems. Orlando is the author of 21 CFR
Part 11-A Complete Guide to International Compliance (Sue Hor-
wood Publishing) and Computer Infrastructure Qualification for FDA
Regulatory Industries (Davis Healthcare International Publishing).
He may be contacted by e-mail at olopez6102@msn.com