[Federal Register Volume 77, Number 54 (Tuesday, March 20, 2012)]
[Rules and Regulations]
[Pages 16158-16163]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-6502]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 211

[Docket No. FDA-1997-N-0518] (formerly 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: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending 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 permitting 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 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 than permitted by current CGMPs.

DATES: This final rule is effective on March 20, 2013, except for the 
amendment adding Sec.  211.122(g)(4), which is effective April 19, 
2012.

FOR FURTHER INFORMATION CONTACT: Brian Hasselbalch, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 4364, Silver Spring, MD 20993-0002, 301-
796-3279, email: [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of July 29, 1997 (62 FR 40489) (the 
proposed rule), FDA proposed to amend the packaging and labeling 
control provisions of the 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, and to permit 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 when cut labeling--single labels 
for individual drug products that are ``cut'' from a sheet or roll of 
labels--is used.
    Persistent problems with drug product mislabeling and subsequent 
recalls led FDA in 1987 and in 1990 to review labeling procedures and 
product recalls. The review identified gang-printed and cut labeling as 
a leading cause of labeling mixups. Gang-printed labeling is defined in 
Sec.  210.3(b)(22) (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 separated from the 
labeling for other products. When labels are gang-printed, the labels 
for different drug products or different strengths for the same drug 
product are processed together, making them especially susceptible to 
mixups. Similarly, cut labeling 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 printer or manufacturer did not detect the error, 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 and cut labeling. Under Sec.  211.122(f), use of gang-printed 
labeling for different drug products, or different strengths or net

[[Page 16159]]

contents of the same product, is prohibited unless the labeling from 
gang-printed sheets is adequately differentiated by size, shape, or 
color. Under Sec.  211.122(g), packaging and labeling operations must 
use one of three special control features if cut labeling is used: (1) 
Packaging and labeling lines must be dedicated to each different 
strength of each different drug product; (2) 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 (3) where labeling is hand-applied, use of 
visual inspection to conduct a 100 percent examination for correct 
labeling during or after completion of finishing operations must be 
performed by one person and independently verified by a second person.
    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. FDA also defined gang-printed labeling at Sec.  
210.3(b)(22). The 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, among other things, that FDA consider 
additional comments on the application of Sec.  211.122(g) to items of 
labeling other than the immediate container label, and requesting 
additional time to obtain, install, or validate equipment necessary to 
comply with the August 3, 1993 final rule. In response to these 
requests, FDA extended the compliance date to August 3, 1995, for Sec.  
211.122(g) as it applies to labeling other than immediate container 
labels, and opened the administrative record for comments on the scope 
of Sec.  211.122(g). All other provisions of the August 3, 1993, final 
rule became effective on August 3, 1994. To adequately assess comments 
received during the extended comment period and provide industry 
additional time to comply with the regulation, FDA published several 
notices extending the compliance date for Sec.  211.122(g), as it 
applies to labeling other than immediate container labels, to August 2, 
1996, to August 1, 1997, and, in the July 29, 1997, Federal Register 
(62 FR 40447), until the effective date of this final rule.
    FDA evaluated the comments received during the extended comment 
period, met with industry representatives, reviewed recall data to 
determine the danger to consumers from errors in different types of 
drug product labeling, and surveyed packaging and labeling control 
technology. On July 29, 1997, FDA issued a proposed rule to narrow the 
scope of Sec.  211.122(g) and to expand the permissible control 
procedures. This rule finalizes the July 29, 1997, proposed rule. As 
described in more detail in section II of this document, the final rule 
adopts the proposed codified without change.

II. Description of the Final Rule

A. Scope of Sec.  211.122

    The first sentence of current states: ``If cut labeling is used, 
packaging and labeling operations shall include one of the following 
special control procedures.'' The final rule amends the first sentence 
of Sec.  211.122(g) 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.'' Thus, instead of applying 
to all types of labeling as required in the August 3, 1993, final rule, 
the control procedures specified in revised Sec.  211.122(g) apply only 
to cut labeling used for immediate container labels, individual unit 
cartons, or multiunit cartons containing immediate containers that are 
not packaged in individual unit cartons. This amendment 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. As explained in the proposed rule, the immediate container 
label is most likely to be read by consumers. The individual unit 
carton labeling 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. When using multiunit cartons 
containing immediate containers that are not packaged in individual 
unit cartons (for example, sterile dosage forms in tray packs in which 
immediate containers lack unit cartons), 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.

B. Special Control Procedures

    Currently, there are three control procedures delineated in Sec.  
211.122(g)(1) through (g)(3): (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. The 
visual inspection must be performed by one person and independently 
verified by a second person. The final rule amends Sec.  211.122(g) to 
add a fourth alternative special control procedure for packaging and 
labeling operations when cut labeling is used that provides for more 
flexibility in determining adequate controls. The fourth control, added 
at Sec.  211.122(g)(4), states: ``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.'' As noted in the proposed rule (62 FR 40489 at 
40491), this additional control procedure is being added because FDA 
believes that this will provide manufacturers with the widest possible 
latitude in selecting appropriate labeling control technologies. It 
will permit the use of a number of automated techniques that will 
physically prevent incorrect labeling from being processed by packaging 
and labeling equipment. 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 equivalent 
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 will 
allow labeling and packaging operations to operate only if correct 
labeling unique to a given product (for example, a specific size) is 
used.

III. Responses to Comments on the Proposed Rule

    FDA received three comments on the proposed rule which raised a 
limited number of issues. The specific issues raised by the commenters 
are described in this section III.
    (Comment 1) One comment said that the final rule should permit all 
effective means of label control, whether they

[[Page 16160]]

involve automated systems or nonautomated systems. The comment said 
that FDA has indicated that both automated and nonautomated systems of 
label control are equally effective in preventing label mixups. The 
comment cited the June 23, 1989, proposed rule and the August 3, 1993, 
final rule, and noted that FDA said that three label control practices 
were not involved in any of the recalls attributed to label mixups 
(i.e., the use of labels differentiated by size, shape, or color; the 
use of dedicated packaging lines; and the use of electronic label 
verification systems that validate the labeling of each product during 
finishing operations (100 percent label inspection)). The comment said 
that these label control practices include both automated (the use of 
electronic label verification systems that validate the labeling of 
each product during finishing operations) and nonautomated (use of 
labels differentiated by size, shape, or color and the use of dedicated 
packaging lines) methods.
    The comment also said that industry's experiences with certain 
electronic and electromechanical control systems have shown 
inconsistent results, and 50-60 percent of the electronic systems that 
were installed during the recent past (the comment was submitted in 
1997) could not be used because of lack of reliability against the 
zero-defect standard. The comment said that some automated systems are 
not robust enough to identify ``bad'' labels 100 percent of the time, 
at certain line speeds and under certain conditions, and the systems 
erred with unacceptable levels of false positives (that is, flagging 
``good'' labels as ``bad'').
    The comment said the special control procedures under proposed 
Sec.  211.122(g) should be modified to allow companies to document a 
system of control that best fits the unique abilities of each 
particular company, without requiring any one particular control system 
(for example, electronic or electromechanical controls) to be used 
across the entire industry. The comment said this approach would allow 
the implementation of technology appropriate for the individual plants 
involved.
    The comment noted that many companies currently use multiple layers 
of control in their labeling operations that have yielded very robust 
systems of total control, and they should not be required to add 
another special layer of control that may not improve their total 
system. The comment stated that FDA should permit additional automated 
and nonautomated methods of control for items of labeling within the 
scope of Sec.  211.122(g). Differentiation by size, shape, or color or 
by any other effective, validated means should be permitted, whether 
automated or not. The comment described other types of layers of 
control that should be permitted, including labeling design to minimize 
mixups, using labeling suppliers that have excellent internal control, 
using label control rooms, proper purging of labeling lines, using 
computerized material requirements planning systems, online checks of 
operations, and reconciliation of labeling.
    Another comment said that the proposed rule would limit industry's 
choice of control measures, and too great an emphasis was placed on 
``high tech'' electronic verification systems. The comment stated that 
traditional methods of label control have proven to be just as 
effective. The comment said that industry is largely operating using 
traditional label control measures along with some high tech electronic 
verification systems as part of an overall system of label control. 
These traditional systems consist of multilevel control measures that 
work together to ensure that label mixups are avoided. The comment said 
that the use of electronic systems alone will not provide this level of 
assurance, because electronic systems are not 100 percent effective and 
often give false alarms in labeling operations that can lead to 
operator complacency and/or inefficient line operation. The comment 
expressed doubt that the use of electronic verification systems would 
improve systems currently in place at its company. The comment 
recommended other control measures as part of an overall system for 
label control that should be considered by FDA, including: (1) An 
ongoing program to assess the label supplier's operations and controls; 
(2) labeling designed to avoid mixups such as differentiation by size, 
shape, and color; (3) procedures addressing art/label approval; (4) a 
multilevel control system that incorporates personnel training, label 
inspection, line clearance, and other control procedures designed to 
avoid mixups; and (5) a validation of such systems that gives assurance 
that label controls are acceptable.
    (Response) First, the Agency believes that it is important to 
emphasize that one of the special controls listed in Sec.  211.122(g) 
must be used only when cut labeling is used for the types of labeling 
described in Sec.  211.122(g). Manufacturers have significant 
additional flexibility to use different labeling controls for other 
types of labeling.
    When cut labeling is used for the identified types of labeling, at 
least one of the special controls in Sec.  211.122(g) must be used. The 
final rule permits the choice of a special control from one of four 
options specified in Sec.  211.122(g)(1) through (g)(4). Two are 
nonautomated controls: dedication of lines (paragraph (g)(1)) and 
visual inspection for hand applied labels (paragraph (g)(3)). Two are 
automated controls: Electronic or electromechanical examination to 
conduct a 100-percent examination for correct labeling during or after 
completion of finishing operations (paragraph (g)(2)), and use of any 
automated technique that physically prevents incorrect labeling from 
being processed by labeling and packaging equipment (paragraph (g)(4)). 
This provides industry with a number of options, including manual, 
electronic, electromechanical, and automated systems. It also permits 
broad discretion to industry to select appropriate electronic or 
automated systems for this purpose, and to ``layer'' different 
controls, if desired, as long as at least one of the options listed in 
paragraph (g) is used as one of the layers.
    However, FDA disagrees that additional nonautomated special 
controls, in addition to dedicated lines or visual inspection, should 
be added to paragraph (g). As we noted in the proposed rule (62 FR 
40489 at 40491), nonautomated (i.e., manual) differentiation of size 
and shape as a labeling control does not provide adequate protection 
from labeling mixups when cut labeling is used. It is the increased 
opportunity for human error afforded by the process of cutting, 
sorting, and subsequent handling of different items of labeling that 
has caused labeling mixups and recalls. One of the goals of this 
rulemaking is to reduce the likelihood for such human error through the 
increased use of automated labeling control systems and through the 
elimination of manual label differentiation by size and shape. In 
addition, in response to the commenter's concern that electronic 
systems are not sufficiently reliable, we believe that development and 
use of advanced code scanning equipment has made many current 
electronic verification systems accurate and reliable. For example, all 
prescription drug products (with limited exceptions), biological 
products, and certain over-the-counter (OTC) drug products are now 
required by 21 CFR 201.25 to bear on the label a bar code containing, 
at a minimum, the drug's NDC (National Drug Code). Electronic systems 
can use these codes to scan the labels as part of

[[Page 16161]]

the label controls. These and other advanced scanning techniques have 
made current electronic systems reliable to the 100 percent standard.
    If cut labeling is used, the choice of one of the four special 
control procedures listed above should allow manufacturers to document 
a system of control that best fits the unique abilities of each 
particular manufacturer without requiring any one particular control 
system to be used. The final rule permits manufacturers considerable 
latitude under Sec.  211.122(g)(1) through (g)(4) in establishing 
control procedures over cut labeling, and is sufficiently flexible to 
permit technological innovation in automated labeling inspection 
systems. For example, under the final rule, a labeling control method 
designed by an individual manufacturer could incorporate electronic or 
electromechanical equipment or the use of a visual inspection to 
conduct a 100 percent examination for correct labeling. Moreover, 
manufacturers are free to use one of the specifically enumerated 
special controls in Sec.  211.122(g) in combination with any other 
special or general labeling controls. The rule merely establishes that, 
at a minimum, one of the four enumerated special controls must be used 
when the identified types of cut labeling are used. Accordingly, many 
of the alternative special and general controls discussed by the 
commenters could also be used in conjunction with one of the enumerated 
special controls.
    The comments suggest that this rule will mandate that manufacturers 
who currently have effective label control systems but are not 
currently using one of the controls enumerated in Sec.  211.122(g)(1) 
through (g)(4) must change their system to include one of the four 
special controls. FDA points out that this would only be true for 
situations where cut labeling is currently being used for those labels 
subject to the enforcement discretion period (labels other than 
immediate container labels) if the manufacturer is not currently 
voluntarily using one of the enumerated special controls. Processes 
using cut labeling for immediate containers labels (the bulk of the 
labels covered by this change) were not subject to enforcement 
discretion and would already be required to use one of the three 
special controls in current Sec.  211.122(g)(1) through (g)(3). The 
only change made by this rule for those labeling processes would be the 
addition of a new option to meet the requirement of subsection (g). 
Those lines would not be required to make any change by this final 
rule.
    (Comment 2) One comment said that the controls for cut labeling 
used for multiunit cartons containing immediate containers that are not 
packaged in individual unit cartons (Sec.  211.122(g)) should not apply 
to OTC drug product shelf-packs. The comment explained that OTC drug 
products are sometimes packaged in what could be called multiunit 
cartons containing immediate containers that are not packaged in 
individual unit cartons. These are often called ``shelf-packs'' or 
``trays.'' The comment gave the following examples: antacid tablets 
packaged in individual rolls and placed in a tray near the checkout of 
a drugstore or supermarket; bottles of sunscreen products displayed in 
an end-unit in a store for convenience and added display space; and 
analgesic powders in printed envelopes placed in a tray to keep them 
upright on the store shelf. The comment noted that for these products 
the immediate containers are not packaged in individual unit cartons. 
However, complete labeling is on the individual packages, and neither 
consumers nor health professionals rely on the information on the tray 
or end-unit to purchase or use the product. The comment said that the 
proposed rule could be interpreted to apply to OTC shelf-packs, trays, 
or end units, but that special control procedures are not needed for 
these products because their labeling is not relied on to purchase the 
products. In addition, because the labeling on the shelf pack, tray, or 
end unit itself does not accompany the product to its point of use, it 
is not relied on by the consumer to use the product. Therefore, the 
comment said, no significant additional protection to the public health 
and safety would result from special control procedures for these 
products. The comment recommended that proposed Sec.  211.122(g) be 
revised to read: ``* * * multiunit cartons containing immediate 
containers of prescription drugs that are not packaged in individual 
unit cartons * * *.''
    (Response) FDA does not agree that the final rule should 
specifically exclude OTC shelf-packs. First, FDA disagrees with the 
assertion that consumers and health professionals do not rely on the 
information on the tray or end-unit to purchase or use the product. 
Although mislabeling of immediate containers poses the most obvious 
threat to public health and safety, a considerable danger is also posed 
by errors in the labeling that influences consumer selection of the 
product at the time of purchase. Indeed, we believe that, in the 
context of shelf-packs, these requirements are more important for OTC 
drugs for which there is not necessarily a health care professional 
involved to help ensure proper product selection. FDA does not agree 
that the rule would significantly affect the use of shelf-packs because 
shelf-packs rely on other packaging and labeling operations and 
infrequently use cut labeling. To the extent that OTC shelf-packs do 
use cut labeling, the special control procedures allow manufacturers 
considerable latitude in establishing appropriate controls.
    (Comment 3) One comment said the rule should not apply to drug 
products in preprinted immediate containers such as tubes, vials, cans, 
bottles, pouches, and blister packages. The comment requested that the 
final rule be revised to specifically exclude preprinted immediate 
containers.
    (Response) FDA agrees that the rule does not apply to drug products 
in preprinted immediate containers because the likelihood of labeling 
mixups appears to be remote and because preprinted drug product 
containers are still subject to existing general labeling controls to 
prevent mixups. Preprinted immediate containers include tubes, vials, 
cans, bottles, pouches, and blister packages where the labeling is 
directly ``inked'' into the package. FDA does not agree that it is 
necessary to amend Sec.  211.122 to expressly exclude drug products in 
preprinted immediate containers because, as adopted in this final rule, 
Sec.  211.122 does not apply to preprinted containers.
    (Comment 4) One comment requested that the rule be finalized only 
as currently applied to immediate container labels in Sec.  211.122(g) 
and not expanded to individual unit cartons or multiunit cartons 
containing immediate containers that are not packaged in individual 
unit cartons.
    (Response) As explained earlier in this preamble, the control 
procedures specified in Sec.  211.122(g) apply to cut labeling used for 
immediate container labels, individual unit cartons, or multiunit 
cartons containing immediate containers that are not packaged in 
individual unit cartons. This 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 
immediate container label is most likely to be read by consumers. The 
individual unit carton labeling 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

[[Page 16162]]

product. When using multiunit cartons containing immediate containers 
that are not packaged in individual unit cartons (for example, sterile 
dosage forms in tray packs in which immediate containers lack unit 
cartons), consumers and health professionals are likely to rely both on 
labeling on the outer multiunit container as well as the labeling on 
the individual drug product immediate containers.
    (Comment 5) One comment questioned the use of the term ``gang-
printed materials'' in the following paragraph of the proposed rule: 
``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 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'' (62 FR 40489 at 
40491 and 40492).
    The comment said that this paragraph appears to equate cut labeling 
with gang-printing. The comment noted that gang-printing is prohibited 
under Sec.  211.122(f): ``Use of gang-printed labeling for different 
drug products, or different strengths or net contents of the same 
product, is prohibited unless the labeling from gang-printed sheets is 
adequately differentiated by size, shape, or color.'' In addition, 
gang-printed labeling is defined in Sec.  210.3(b)(22) as ``labeling 
derived from a sheet of material on which more than one item of 
labeling is printed.'' The comment noted that the printing of 
repetitions of the same item of labeling on the same sheet results in 
cut labeling, as the individual repetitions of the item are cut from 
the sheet for use. The comment said that this is not gang-printing and 
does not present the same opportunity ``for human error afforded by the 
process of cutting, sorting, and subsequent handling of different items 
of labeling'' as does gang-printing, because the labeling is all 
identical.
    (Response) FDA acknowledges that the distinction between ``gang-
printed labeling'' and ``cut labeling'' in the July 29, 1997, proposed 
rule (62 FR 40490) may have caused confusion among some readers. Gang-
printed labeling, as explained earlier in this preamble, is defined in 
Sec.  210.3(b)(22) (21 CFR 210.3(b)(22)) as labeling derived from a 
sheet of material on which more than one item of labeling is printed. 
For example, a sheet of material that contains labeling for different 
strengths of a drug product is considered to be gang-printed. In 
contrast, cut labeling, as described in the August 3, 1993, final rule 
(58 FR at 41350), refers to items of labeling that have been detached 
or ``cut'' from printed stock material. This stock material may or may 
not be gang-printed; it may contain labeling for different drug 
products or different strengths of the same drug product or it may 
contain identical labeling for the same drug product. The printing 
method of the stock material has no bearing on whether labeling is 
considered to be cut labeling. The defining feature of cut labeling is 
simply that it is ``cut.'' After being cut, such labeling is commonly 
sorted by type or strength of drug product (if it is not identical), 
placed into separate, corresponding stacks, and then transported to the 
packaging and labeling lines for application to the appropriate 
product. Cut labeling is problematic because the items, when cut and 
placed into individual stacks for application to different drug 
products, are easily mixed up. FDA found that stacks of labeling of 
similar size, shape, and color could easily be intermixed and, if the 
manufacturer did not detect the error, incorrect labeling could be 
applied and a mislabeled drug product distributed.
    (Comment 6) One comment said that Sec.  211.122(g)(3) should be 
revised to include the sentence: ``Such a 100 percent examination must 
be conducted by one person and independently verified by a second 
person.'' The comment said by omitting this phrase the public might be 
led to the presumption that the ``verification by a second person'' is 
no longer required.
    (Response) FDA notes that it did not propose to amend Sec.  
211.122(g)(3), nor is that section being amended by this final rule. 
Moreover, because the first sentence of Sec.  211.122(g)(3) already 
states that ``a 100-percent examination'' for correct labeling is 
required, repeating the phrase ``100-percent'' in the second sentence 
of paragraph (3), as proposed by the commenter, would be redundant. 
Therefore, the final rule does not adopt the change suggested by the 
commenter.
    (Comment 7) One comment said that the proposed compliance date of 6 
months after publication of the final rule should be extended to 1 year 
to adequately implement any new controls.
    (Response) As requested by the comment, we are providing an 
effective date of 1 year from the date of publication of this final 
rule as it applies to labels that had not previously been covered by 
this regulation. The application of Sec.  211.122(g) to labeling other 
than labeling used for immediate container labels has been stayed since 
August 3, 1994. Although it lifts the stay, the final rule also narrows 
the applicability of Sec.  211.122(g) so that, in addition to immediate 
container labeling, the only other labeling that is subject to final 
Sec.  211.122(g) is cut labeling used for individual unit cartons, or 
multiunit cartons containing immediate containers that are not packaged 
in individual unit cartons. We believe 1 year will be sufficient to 
permit companies to adopt an appropriate control from Sec.  
211.122(g)(1) through (g)(4) for those limited additional categories of 
cut labeling.
    The shorter implementation period applicable to cut labeling used 
for immediate container labels (which make up the majority of cut 
labeling used) reflects the fact that sections 211.122(g)(1) through 
(g)(3) as they apply to such labels have been effective since August 3, 
1994. As to those labels, this final rule merely adds an additional 
control option for the appropriate use of cut labeling (i.e., Sec.  
211.122(g)(4)). Accordingly, as to those labels, we are making this 
rule effective 30 days after its publication in the Federal Register. 
If they wish, labelers may continue to use one of the appropriate 
controls listed in Sec.  211.122(g)(1) through (g)(3) that have been 
applicable to those labels since 1994. Adoption of the additional 
control option in Sec.  211.122(g)(4) added by this final rule is 
purely voluntary but, since the regulation provides an alternative 
method of compliance, there is no reason to delay its applicability 
beyond the statutory 30-day period.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct 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 final rule is not a significant 
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this rule reduces the scope of the 1993 
final rule and

[[Page 16163]]

provides manufacturers greater flexibility to meet regulatory 
requirements, the Agency certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $136 million, using the most current (2010) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The purpose of this final rule is to protect consumers from those 
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. This 
rule amends the 1993 final rule by limiting the scope to cut labeling 
for immediate container labels, individual unit cartons, and multiunit 
cartons containing immediate containers that are not packaged in 
individual unit cartons. This 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 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.

V. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) 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.

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, 21 CFR part 
211 is amended as follows:

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

0
1. The authority citation for 21 CFR part 211 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 
U.S.C. 216, 262, 263a, 264.


0
2. Section 211.122 is amended by revising the introductory text of 
paragraph (g) and by adding 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: March 13, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-6502 Filed 3-19-12; 8:45 am]
BILLING CODE 4160-01-P