[Federal Register Volume 62, Number 145 (Tuesday, July 29, 1997)]
[Proposed Rules]
[Pages 40489-40492]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19817]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 211
[Docket No. 97N-0300]
Current Good Manufacturing Practice in Manufacturing, Processing,
Packing, or Holding of Drugs; Revision of Certain Labeling Controls
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the packaging and labeling control provisions of the current good
manufacturing practice (CGMP) regulations for human and veterinary drug
products by limiting the application of special control procedures for
the use of cut labeling to immediate container labels, individual unit
cartons, or multiunit cartons containing immediate containers that are
not packaged in individual unit cartons. FDA is also proposing to
permit the use of any automated technique,
[[Page 40490]]
including differentiation by labeling size and shape, that physically
prevents incorrect labeling from being processed by labeling and
packaging equipment when cut labeling is used. This action is intended
to protect consumers from labeling errors more likely to cause adverse
health consequences, while eliminating the regulatory burden of
applying the rule to labeling unlikely to reach or adversely affect
consumers. This action is also intended to permit manufacturers to use
a broader range of error prevention and labeling control techniques.
DATES: Comments by October 27, 1997. FDA proposes that any final rule
that may issue based on this proposal become effective 6 months after
its date of publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville MD 20857.
FOR FURTHER INFORMATION CONTACT:
Thomas C. Kuchenberg, Center for Drug Evaluation and Research (HFD-
7), 5600 Fishers Lane, Rockville, MD 20857, 301-594-5621 (Internet
electronic mail: kuchenbergt@cder.fda.gov); or
Paul J. Motise, Center for Drug Evaluation and Research (HFD-325),
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,
301-594-1089 (Internet electronic mail: motise@cder.fda.gov).
SUPPLEMENTARY INFORMATION:
I. Background
Persistent problems with drug product mislabeling and subsequent
recalls in the late 1980's led FDA to review labeling procedures and
product recalls. The review identified gang-printed or cut labeling as
a leading cause of labeling mixups. Gang-printed labeling is defined in
21 CFR 210.3(b)(22) as labeling derived from a sheet of material on
which more than one item of labeling is printed. Each sheet includes
labeling for a variety of products and, because of this, labeling for
individual drug products must be ``cut'' or separated from the labeling
for other products. Cut labeling for individual drug products is
commonly placed in separate stacks before being transported to
packaging and labeling lines for application to appropriate products.
FDA found that stacks of labeling of similar size, shape, and color
could easily be intermixed and, if the error was not detected by the
printer or manufacturer, incorrect labeling could be applied and a
mislabeled drug product distributed.
To reduce the frequency and likelihood of such mislabeling, FDA, in
the Federal Register of August 3, 1993 (58 FR 41348), amended the
packaging and labeling control provisions of the CGMP regulations in
part 211 (21 CFR part 211) to provide specific conditions for the use
of all gang-printed or cut labeling (hereinafter referred to as the
1993 final rule). Under Sec. 211.122(g), packaging and labeling
operations must use one of three special control features if cut
labeling is used. Packaging and labeling lines must be dedicated to
each different strength of each different drug product, appropriate
electronic or electromechanical equipment must be used to conduct a
100-percent examination for correct labeling during or after completion
of finishing operations, or, where labeling is hand-applied, a 100-
percent visual inspection must be conducted by one person and
independently verified by a second person. Appropriate electronic or
electromechanical equipment typically consists of systems that scan
identity codes printed on the labeling. If the wrong code is detected,
the incorrect labeling is ejected from the labeling line.
To further limit the potential for mislabeling, FDA also required
written procedures for the identification and handling of filled drug
product containers not immediately labeled (Sec. 211.130(b)). FDA also
amended Sec. 211.125(c) to exempt manufacturers that use automated 100-
percent examination for correct labeling from the label reconciliation
requirements.
The 1993 final rule applied to all types of labeling including
product inserts, multiunit containers packaged in individual
containers, and shipping containers.
In May 1994, FDA received two citizen petitions from several trade
associations requesting that the agency extend the effective date of
the rule and reopen the administrative record to receive additional
comments on the application of Sec. 211.122(g) to items of labeling
other than the immediate container label. The petitions stated that
additional time was needed to obtain, install, or validate equipment
necessary to comply with the rule. The citizen petitions also contended
that the final rule inappropriately expanded the scope of
Sec. 211.122(g) from immediate container labels to all drug product
labeling.
In the Federal Register of August 2, 1994 (59 FR 39255), FDA
extended the compliance date for Sec. 211.122(g) as it applies to
labeling other than immediate container labels, and opened the
administrative record through October 4, 1994, for comments on the
scope of Sec. 211.122(g). All other provisions of the final rule became
effective on August 3, 1994. FDA further extended the compliance date
to August 2, 1996, in the Federal Register of April 28, 1995 (60 FR
20897), and to August 1, 1997, in the Federal Register of July 19, 1996
(61 FR 37679).
Elsewhere in this issue of the Federal Register, FDA is announcing
a continuation of the partial extension of the compliance date until
the effective date of the regulation finalizing this proposed rule.
FDA received 14 comments during the extended comment period. Those
comments that addressed the scope of Sec. 211.122(g) are discussed
below:
Concerning the question of whether Sec. 211.122(g) should be
applied to items of labeling other than the immediate container label,
most comments favored restricting application of the regulation either
to immediate container labels or to some category or subset of overall
product ``labeling.'' Several comments requested that manual
differentiation by size, shape, and color as well as other validated
labeling control methods be added to the list of special control
procedures listed in Sec. 211.122(g). One comment asserted that
specifying the use of electronic or electromechanical methods as a
special control procedure unnecessarily limits the options of firms
packaging pharmaceuticals. A number of comments stated that, with
appropriate controls, the use of size, shape, or color differentiation
as a manual labeling control measure is adequate to prevent labeling
mixups. A number of comments asked for clarification as to which types
of cut labeling would require the use of an automated verification
system. Some comments requested exemptions for specific labeling. One
comment requested that hand-labeling operations be specifically
excluded from the requirement for electronic inspection, regardless of
the volume of the manufacturing operation, if labeling is inspected
manually. Another comment recommended procedures to be used when cut
labeling is applied to dosage-form packages assembled in stages.
In light of comments received during the extended comment period,
FDA held a number of meetings with representatives of the labeling
industry and others to examine control options available through
current technology.
After evaluating the comments, reviewing the recall data, and
surveying packaging and labeling control technology, FDA has determined
that the scope of Sec. 211.122(g) should be
[[Page 40491]]
narrowed and the permissible control procedures expanded. FDA is
proposing to limit the scope of the cut labeling provision to immediate
container labels, individual unit cartons, or multiunit cartons
containing immediate containers that are not packaged in individual
unit cartons. FDA is also proposing to expand the permissible control
procedures to include the use of any automated technique, including
differentiation by labeling size and shape, that physically prevents
incorrect labeling from being processed by labeling and packaging
equipment.
II. Description of the Proposed Rule
A. Scope
The first sentence of current Sec. 211.122(g) states: ``If cut
labeling is used, packaging and labeling operations shall include one
of the following special control procedures''.
FDA is proposing to limit the scope of Sec. 211.122(g) by revising
this sentence to state: ``If cut labeling is used for immediate
container labels, individual unit cartons, or multiunit cartons
containing immediate containers that are not packaged in individual
unit cartons, packaging and labeling operations shall include one of
the following special control procedures''.
FDA's main concern in proposing controls for cut labeling is to
reduce the public health and safety risk stemming from drug product
labeling mixups. The petitions and comments on the scope of
Sec. 211.122(g) asserted that the economic burden on industry would be
great if the provision applied to all labeling, and questioned whether
including such types of labeling as shipping cartons, that are unlikely
to be read by consumers, would provide any significant additional
protection to public health and safety.
FDA has examined these comments and other information and agrees
that the greater the likelihood that consumers will read incorrect
labeling information, the greater the danger that the drug product will
be used according to the mislabeled instructions. Thus, the immediate
container label poses the most obvious threat. In addition, individual
unit carton labeling could pose an equal danger because it is the
outermost container in which a drug product is commonly marketed at
retail and many consumers read this labeling when deciding whether to
purchase a product. Moreover, because the individual unit carton
labeling may be in a larger type or otherwise easier to read than the
immediate container label, consumers may keep the carton and refer to
it when using the drug product. A similar concern applies to multiunit
cartons containing immediate containers that are not packaged in
individual unit cartons (e.g., sterile dosage forms in tray packs in
which immediate containers lack unit cartons), because consumers and
health professionals are more likely to rely on labeling on the outer
multiunit container than to examine the labeling on the individual drug
product immediate containers. In deciding whether to limit the scope of
the labeling control provisions, FDA reviewed recall data to determine
the danger to consumers from errors in different types of drug product
labeling.\1\ This examination indicated that there have been Class I
and Class II recalls involving immediate containers, individual unit
cartons containing the drug product in its immediate container, and
multiunit cartons containing immediate containers that are not packaged
in individual unit cartons. Recalls due to the use of the wrong inserts
or outserts (printed information about a drug product attached to the
exterior of the product) and recalls of multiunit or shelf-pack
containers holding unit cartons, shipping or intermediate containers,
and shipping cases have all been designated as Class III recalls, i.e.,
situations in which the labeling error is generally not likely to cause
adverse health consequences.
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\1\ Unless ordered by a court, a drug recall is a voluntary
action whereby manufacturers remove from the market drugs that are
found by FDA to be marketed in violation of laws administered by the
agency.
Under FDA's current policy, the agency assigns a numerical
designation to each product recall to indicate the relative degree
of hazard presented by the product being recalled. A Class I recall
involves the greatest potential health threat and a Class III recall
involves the least serious health threat.
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Therefore, FDA is proposing that the control procedures specified
in Sec. 211.122(g) apply only to immediate container labels, individual
unit cartons, or multiunit cartons containing immediate containers that
are not packaged in individual unit cartons. This action is intended to
protect consumers from labeling errors that are more likely to cause
adverse health consequences, while eliminating the regulatory burden of
applying the rule to labeling unlikely to reach or adversely affect
consumers. The proposal is also intended to eliminate any confusion
about the scope of the cut labeling control provisions and allow an
additional opportunity for public comment.
Although a number of types of labeling would not be subject to this
proposed rule, it is important to note that any labeling mixup can
result in a misbranded drug product. FDA encourages manufacturers to
take steps to protect the integrity of their labeling operations.
Although not proposed in this rulemaking, FDA encourages firms to: (1)
Convert all articles of cut labeling to roll labeling where possible
(such as the use of roll inserts or roll label/insert combinations);
(2) use online printing methods; or (3) adopt 100-percent automated
verification systems for all items of cut labeling.
B. Special Control Procedures
Under Sec. 211.122(g)(1), (g)(2), and (g)(3), packaging and
labeling operations must include one of the following special control
procedures when cut labeling is used: (1) Dedication of labeling and
packaging lines to each different strength of each different drug
product; (2) use of appropriate electronic or electromechanical
equipment to conduct a 100-percent examination for correct labeling
during or after completion of finishing operations; or (3) use of
visual inspection to conduct a 100-percent examination for correct
labeling during or after completion of finishing operations for hand-
applied labeling.
FDA is proposing to add a fourth special control procedure at
Sec. 211.122(g)(4): ``Use of any automated technique, including
differentiation by labeling size and shape, that physically prevents
incorrect labeling from being processed by labeling and packaging
equipment.'' FDA is proposing this additional control procedure because
the agency believes that a number of other automated techniques will
also physically prevent incorrect labeling from being processed by
packaging and labeling equipment, and would provide manufacturers with
the widest possible latitude in selecting appropriate labeling control
technologies. A labeling control method using size and shape as part of
an automated technique that prevents incorrect labeling from being
processed by labeling and packaging lines provides the same labeling
control protection, through prevention, as do the other special control
procedures through surveillance or dedication of labeling and packaging
lines. An acceptable automated technique would allow labeling and
packaging operations to operate only if correct labeling unique to a
given product (e.g., a specific size) is used.
FDA notes, however, that nonautomated (i.e., manual)
differentiation of size and shape as a labeling control does not
provide adequate protection from labeling mixups. It is the increased
opportunity
[[Page 40492]]
for human error afforded by the process of cutting, sorting, and
subsequent handling of different items of labeling from gang-printed
materials that has caused labeling mixups and recalls. One of the goals
of this proposed rulemaking is to reduce the likelihood for such human
error through the use of automated labeling control systems.
III. Environmental Impact
The agency has determined under 21 CFR 25.24 (a) (10) that this
action is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
IV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (2 U.S.C. 1532). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order.
The proposed rule substantially reduces the scope of the 1993 final
rule, which applied to all cut labeling, so that the proposed rule only
applies to cut labeling for immediate container labels, individual unit
cartons, or multiunit cartons containing immediate containers that are
not packaged in individual unit cartons. This proposed rule also
increases flexibility for firms selecting special labeling control
procedures by adding a provision for the use of any automated
technique, including differentiation by size and shape, that physically
prevents incorrect labeling from being processed by labeling and
packaging equipment. Therefore this proposed rule is expected to have a
positive economic impact on drug manufacturers that would otherwise be
subject to the more stringent requirements under current regulations.
Mislabeled drug products may pose a threat to public health, lead
to extremely costly product recalls, and create significant product
liability. As a result, FDA believes that a large number of firms
already use the labeling control procedures proposed in this
rulemaking. The agency concludes that the proposed rule is not a major
rule as defined in Executive Order 12866 because the labeling control
revisions significantly reduce the scope of the current rule and
provide manufacturers with greater flexibility in selecting special
control procedures if cut labeling is used. Further, the agency
certifies that the proposed rule is not expected to have a significant
economic impact on a substantial number of small entities, as defined
by the Regulatory Flexibility Act.
The Unfunded Mandates Reform Act requires that agencies prepare an
assessment of anticipated costs and benefits before proposing any rule
that may result in an annual expenditure by State, local and tribal
governments, in the aggregate, or by the private sector, of $100
million (adjusted annually for inflation). Because this proposed rule
will not impose a cost of $100 million or more on any governmental
entity or the private sector, no budgetary impact statement is
required.
V. Request for Comments
Interested persons may, on or before October 27, 1997, submit to
the Dockets Management Branch (HFA-305), Food and Drug Administration,
rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857, written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects in 21 CFR Part 211
Drugs, Labeling, Laboratories, Packaging and containers,
Prescription drugs, Reporting and recordkeeping requirements,
Warehouses.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 211 be amended as follows:
PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
1. The authority citation for 21 CFR part 211 continues to read as
follows:
Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
355, 356, 357, 360b, 371, 374).
2. Section 211.122 is amended by revising the introductory text of
paragraph (g) and by adding new paragraph (g)(4) to read as follows:
Sec. 211.122 Materials examination and usage criteria.
* * * * *
(g) If cut labeling is used for immediate container labels,
individual unit cartons, or multiunit cartons containing immediate
containers that are not packaged in individual unit cartons, packaging
and labeling operations shall include one of the following special
control procedures:
* * * * *
(4) Use of any automated technique, including differentiation by
labeling size and shape, that physically prevents incorrect labeling
from being processed by labeling and packaging equipment.
* * * * *
Dated: July 22, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-19817 Filed 7-28-97; 8:45 am]
BILLING CODE 4160-01-F
