Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; Revision of Certain Labeling Controls

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

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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

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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