[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: [email protected]); 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: [email protected]).

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