Bar Code Label Requirement for Human Drug Products and Biological Products

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 606, and 610

[Docket No. 2002N-0204]

Bar Code Label Requirement for Human Drug Products and Biological Products

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Final rule.

SUMMARY:

The Food and Drug Administration (FDA) is issuing a new rule to require certain human drug and biological product labels to have bar codes. The bar code for human drug products and biological products (other than blood, blood components, and devices regulated by the Center for Biologics Evaluation and Research) must contain the National Drug Code (NDC) number in a linear bar code. The rule will help reduce the number of medication errors in hospitals and other health care settings by allowing health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is being given to the right patient at the right time. The rule also requires the use of machine-readable information on blood and blood component container labels to help reduce medication errors.

DATES:

Effective Date

: This rule is effective on April 26, 2004.

Compliance Dates

: Drug products that receive approval on or after the rule's effective date must comply with the bar code requirement within 60 days after the drug's approval date. Drug products that received approval before the final rule's effective date must comply with the bar code requirement within 2 years after the final rule's effective date. Specific information on how the rule will be implemented can be found in section II.I of this document

.

FOR FURTHER INFORMATION CONTACT:

Philip L. Chao, Office of Policy and Planning (HF-23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-0587.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction

II. Comments on the Proposed Rule and FDA's Responses

A. Who Is Subject to the Bar Code Requirement? (§ 201.25(a))

B. What Products Must Have a Bar Code? (§ 201.25(b))

1. Should Prescription Drug Samples Be Excluded From the Rule?

2. Which OTC Drug Products Must Have a Bar Code?

3. Must Vaccines Have a Bar Code?

4. What Other Types of Drugs Should Be Subject to a Bar Code Requirement?

5. Should Medical Devices Be Excluded From the Rule?

C. What Must the Bar Code Contain? (§ 201.25(c)(1))

1. Should We Require the Bar Code to Contain the NDC Number?

2. Should the Bar Code Contain Lot Number and Expiration Date Information?

3. Can Information Be Omitted from the Label to Accommodate the Bar Code?

D. Does the Rule Require a Specific Type of Bar Code? (§ 201.25(c)(1))

1. Should the Rule Require Linear Bar Codes?

2. Should the Rule Impose Any Conditions on the Bar Code?

E. Where Does the Bar Code Go? (§ 201.25(c)(2))

F. Must Blood and Blood Components Bear “Machine-Readable” Information? (§ 606.121(c)(13))

G. Must Biological Products Have a Bar Code? (§ 610.67)

H. What Other Comments Did We Receive?

1. Comments Seeking More Action by FDA

2. Comments Relating to Bar Code Problems or Quality

3. Comments Regarding FDA's Future Involvement with Bar Codes

4. Miscellaneous Comments

I. How Will We Implement the Rule?

III. Legal Authority

IV. Environmental Impact

V. Paperwork Reduction Act of 1995

A. What Is the Estimated Information Collection Burden?

B. What Comments Did We Receive on Our Estimates?

VI. Federalism

VII. Analysis of Impacts

A. Introduction

B. Objective of the Rule

C. Estimate of Preventable Adverse Drug Events and Acute Hemolytic Transfusion Reactions

D. The Final Rule

E. Description of Affected Sectors

1. Current Machine-Readable Technologies

2. Manufacturers and Packagers of Affected Products

3. Retail Outlets

4. Hospitals

5. Nursing Homes and Long-Term Care Facilities

6. FDA Oversight and Responsibilities

F. Regulatory Costs of the Final Rule

1. Introduction

2. Costs to Manufacturers and Packagers of Affected Products

3. Costs to Retailers and Distributors

4. Costs to Hospitals

5. Costs to the Food and Drug Administration

6. Total Regulatory Costs

G. Other Anticipated Expenditures

H. Reduction in Preventable Adverse Drug Events and Preventable Acute Hemolytic Transfusion Reactions

I. Value of Avoided ADEs and AHTRs

1. Value of Avoided ADEs

2. Value of Avoided AHTRs

J. Aggregate Benefit of Avoiding ADEs and AHTRs

K. Cost Effectiveness of Bar Coding

L. Other Benefits of Bar Code Technology

M. Distributional Effects of Bar Code Technology

N. Comparison of Costs, Expenditures, and Benefits

O. Uncertainty and Sensitivity

1. Voluntary Share of Labeling Costs

2. Packaging Decisions

3. Implementation Period

4. Value of Mortality Associated with ADEs

5. Value per QALY

6. Boundary Analysis

7. Hospital Response Rates

8. Hospital Intercept Rates with Machine-Readable Technology

9. Productivity Losses in Hospital Wards

10. Investments by Hospital Size

P. Small Business Analysis and Discussion of Alternatives

1. Affected Sectors and Nature of Impacts

2. Alternatives

3. Outreach

4. What Comments Did We Receive on Our Economic Analysis?

Q. Conclusion

R. References

I. Introduction

In the

Federal Register

of March 14, 2003 (68 FR 12500), FDA (we) published a proposed rule that would require certain human drug and biological product labels to have a linear bar code (the March 2003 proposal). The proposal would require the bar code to contain the drug's NDC number. For blood and blood components, the proposal would require the use of machine-readable information on the container label. Our intent was to help reduce the number of medication errors in hospitals and health care settings by allowing health care professionals to use bar code scanning equipment to verify that the right drug, in the right dose and right route of administration, is being given to the right patient at the right

time. For blood and blood components, the machine-readable information would perform a similar function and help prevent errors such as transfusion errors.

The preamble to the March 2003 proposal described the events that led us to issue the proposal (see 68 FR 12500 through 12503), and we refer readers to that preamble if they wish to obtain details on the events, recommendations, meetings, and literature that shaped the proposed rule. In brief, medication errors are a serious public health problem, and putting bar codes on drug products is expected to significantly reduce medication errors. Medication errors can occur at several points from the time the physician prescribes the drug to a patient to the time when the patient receives the drug. For example, the physician may write a prescription for the right drug, but in the wrong dose. The pharmacist might misread the prescription and provide the wrong drug, or read the prescription correctly and dispense the wrong drug. The health care professional administering the drug might give it to the wrong patient or give it to the right patient, but at the wrong time or in the wrong dose. Although most medication errors do not result in harm to patients, medication errors can result and have resulted in serious injury or death. Medication errors also represent a significant economic cost to the United States; one article published in 2001 (Ref. 30) estimated the direct cost to be $177.4 billion, while another (Ref. 31) estimated the cost of preventable adverse drug events in hospitalized patients to be $5,857 for each adverse drug event, with the estimated annual costs for preventable adverse drug events for a 700-bed hospital to be $2.8 million.

Bar codes can help reduce or detect potential medication errors by enabling health care professionals to check whether they are giving the right drug via the right dose and right route of administration to the right patient at the right time. The bar codes would be part of a system, along with bar code scanners and computerized databases, where:

• A patient would have his or her drug regimen information entered into a computerized database.

• Each drug would have a bar code. The bar code would provide unique, identifying information about the drug that is to be dispensed to the patient.

• In hospitals, health care professionals, such as pharmacists and nurses, would use bar code scanners (also called bar code readers) to read the bar code on the drug before dispensing the drug to the patient and to read a bar coded wristband on the patient before giving the drug to the patient. In an outpatient setting, the health care professional (such as a pharmacist) could scan the bar code on the drug and compare the scanned information against the patient's electronic prescription information before giving the drug to the patient.

• The bar code scanner's information would go to the computer where it would be compared against the patient's drug regimen information to check whether the right patient is receiving the right drug (including the right dose of that drug in the right route of administration). The system could also be designed to check whether the patient is receiving the drug at the right time.

• If the identity of the health care professional administering the drug were desired, each health care professional could also have a bar code. The health care professional would scan his or her own bar code before giving the drug to the patient.

Bar codes can also complement other efforts to reduce medication errors, such as computer physician order entry (CPOE) systems (where a physician enters orders into a computer instead of writing them on paper, and the order can be checked against the patient's records for possible drug interactions, overdoses, and patient allergies) and pharmacy-based computer systems that use a bar-coded NDC number to verify that a consumer's prescription is being dispensed with the correct drug.

We (FDA) held a public meeting on July 26, 2002, to discuss a possible rule to require bar codes on human drug products, blood, and blood components (see 67 FR 41360, June 18, 2002). Nearly 400 individuals attended that public meeting, and many submitted comments to us. We then published the March 2003 proposal. The March 2003 proposal would create a new § 201.25 (21 CFR 201.25) entitled “Bar Code Label Requirements.” (For biological products other than blood and blood components, the bar code requirement would exist through a cross-reference at a new § 610.67 (21 CFR 610.67.) The proposal also would amend the preexisting, voluntary provision regarding “machine-readable” symbols on blood and blood component container labels at § 606.121(c)(13) (21 CFR 606.121(c)(13) to require the use of machine-readable information.

We received approximately 190 comments on the proposal, and almost all comments supported the rule in whole or in part. For example, one comment said that “FDA is to be highly commended for both the proposed regulation and the process leading to it” while another said that the rule was an “excellent step toward reducing medication errors.” Other comments reported favorably on their own experiences with bar codes on drugs. One comment from a hospital said that the hospital had recently begun bedside verification of medications, using bar codes, and that the bar codes were a valuable tool for reducing medication errors. A comment from a health professional noted that his health care system used bar codes to dispense patient medications and those using robots to dispense medications reduced the manual error dispensing rate by 50 percent.

A few comments, however, were skeptical about the value of bar coding drugs. For example, one comment described problems associated with installing new technology in old buildings. The comment also feared that our rule would cause hospitals to lose their accreditation if they did not adopt bar coding technology. Another comment expressed concern about the impact on nurses' workloads. The comment said bar codes on drugs could cause nurses to spend more time administering medications because of scanning errors or problems with the bar code, but concluded that “the ultimate outcomes will be worth the investment for the manufacturers, the providers, and ultimately the patients.”

After reviewing the comments, FDA made several changes to the rule. The principal changes between the proposed and final rule are as follows:

Proposed Rule

Final Rule

Would apply to prescription drugs (except for samples) and to over-the-counter drugs commonly used in hospitals and dispensed pursuant to an order

Applies to most prescription drugs (except for samples, allergenic extracts, intrauterine contraceptive devices that are regulated as drugs, medical gases, radiopharmaceuticals, low-density polyethylene form fill and seal containers, and prescription drugs sold directly to patients) and to over-the-counter drugs commonly used in hospitals and dispensed under an order. We explain the reasons for exempting certain prescription drugs in section II.B.4 of this document.

Did not contain a general exemption provision

Contains a limited, general exemption provision. We explain the reasons for creating a general exemption provision in section II.B.4.c of this document.

Would require a linear bar code that meets Uniform Code Council standards

Requires a linear bar code that meets Uniform Code Council standards or Health Industry Business Communications Council standards. We explain the reasons for this change at section II.D.1 of this document.

Would create a 3-year implementation period

Establishes different compliance dates depending on when a drug was approved. In general, the rule is effective 60 days after date of publication in the

Federal Register

. If a drug receives approval on or after the effective date, it must comply with the bar code requirement within 60 days of the drug's approval date. If the drug received approval before the rule's effective date, it must comply with the bar code requirement within 2 years of the final rule's effective date. For blood and blood components, a 2 year compliance date exists. We explain the implementation of this rule at section II.I of this document.

We describe and respond to the comments in section II of this document. To make it easier to identify comments and our responses, the word “Comment,” in parentheses, will appear before the comment's description, and the word “Response,” in parentheses, will appear before our response. We have also numbered each comment to help distinguish between different comments. The number assigned to each comment is purely for organizational purposes and does not signify the comment's value or importance or the order in which it was received.

II. Comments on the Proposed Rule and FDA's Responses

A. Who Is Subject to the Bar Code Requirement? (§ 201.25(a))

Under proposed § 201.25(a), manufacturers, repackers, relabelers, and private label distributors of human prescription drug products and over-the-counter (OTC) drug products regulated under the Federal Food, Drug, and Cosmetic Act (the act) or the Public Health Service Act (PHS Act) would be subject to the bar code requirement unless they are exempt from the establishment registration and drug listing requirements in section 510 of the act (21 U.S.C. 360).

In the preamble to the proposed rule (68 FR 12500 at 12503), we acknowledged that some hospitals place bar codes on drugs themselves and have reduced their medication error rates significantly, but we stated that requiring manufacturers, repackers, relabelers, and private label distributors to bar code their own products should be more efficient and result in better quality bar codes because manufacturers, repackers, relabelers, and private label distributors generally have sophisticated manufacturing processes, labeling machinery, and quality control systems that hospitals cannot afford. We added that bar coding by third parties (such as hospitals) could increase the possibility of a label error through the attachment of the wrong bar code and could lead to inconsistent bar code quality; in fact, one organization that submitted a comment at our public meeting on July 26, 2002, estimated the error rate in hospital labeling to be approximately 17 percent nationwide.

We also stated that requiring manufacturers, repackers, relabelers, and private label distributors to bar code their own products and to use the same bar coding standard would result in a more uniform bar coding system that could be used regardless of a patient's or hospital's location in the United States, and that this uniformity would also make it easier for health care professionals to train themselves on bar coding procedures and technique and make it easier and less expensive for hospitals to buy bar coding equipment.

(Comment 1) One comment stated that hospital pharmacies should be subject to the bar code requirements. The comment explained that hospitals frequently compound drugs for pediatric use and that omitting such compounded drugs from the rule would leave “infants and children without the protections that bar codes are intended to provide.”

Another comment argued that we should exempt nuclear pharmacies from the rule. The comment claimed that a bar code requirement would subject hospital personnel and employees to additional radiation (because they would have to scan the bar codes).

(Response) Section 510(g)(1) of the act states that pharmacies

which maintain establishments in conformance with any applicable local laws regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon prescriptions of practitioners licensed to administer such drugs or devices to patients under the care of practitioners in the course of their professional practice, and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail

do not have to register their establishments or list their products with FDA. Thus, if a pharmacy is exempt, under section 510(g)(1) of the act, from our establishment registration and drug listing requirements, the pharmacy is not subject to the bar code requirements.

We also note that drugs compounded at pharmacies generally would not have NDC numbers. NDC numbers are assigned to drugs that are listed under section 510(j) of the act, but, as we

explained earlier, section 510(g)(1) of the act would exempt a pharmacy from the registration and listing requirements. Consequently, a compounded drug would not be listed, would not be assigned an NDC number, and would therefore lack the information required to be in the bar code.

Regarding the comment claiming that a bar code requirement would lead to greater radiation exposure for nuclear pharmacy employees, the comment did not provide any evidence or data to show that using a bar code scanner would constitute a significant or even appreciable risk or that bar code scanners would undermine or compromise any existing measures taken to protect such employees from radiation exposure. Nevertheless, as we explain in our response to comment 24 in section II.B.4.b. of this document, we have decided to exempt radiopharmaceuticals from the bar code requirement.

(Comment 2) One comment said we should exempt hospitals, institutional providers, and large clinics from the rule. The comment interpreted the rule's reference to repackers and relabelers as covering hospitals and other providers and said that hospitals and other providers would still have to repack and relabel drugs (such as intravenous solutions and mixes). The comment declared it would be “unrealistic” to expect hospitals and other providers to obtain NDC labeler codes and “participate in the NDC system.”

In contrast, several comments said we should extend the rule to hospitals or expressed disappointment that the rule did not require hospitals to use bar codes. For example, one comment said the Federal Government should establish requirements so that hospitals would have to adopt technologies to use the bar codes. Another comment said that we should “encourage,” but not require, hospitals to use bar code technology. The comment said that most hospitals would find it difficult to adopt bar code technology due to the age of their buildings and their construction.

Another comment asked us to clarify that relabeled, repackaged, or privately labeled drugs must have their own NDC numbers. The comment said that hospitals and pharmacies must not use the same NDC number that the drug's manufacturer used.

(Response) Some comments appear to have misinterpreted the rule. Repackers, relabelers, and private label distributors that are exempt from the establishment registration and drug listing requirements in section 510 of the act (see 68 FR 12500 at 12503; see also proposed § 201.25(a)) are not subject to the bar code requirements. Hospitals, clinics, and public health agencies that “maintain establishments in conformance with any applicable local laws regulating the practices of pharmacy or medicine and that regularly engage in dispensing prescription drugs * * * upon prescription of practitioners licensed by law to administer these drugs to patients under their professional care” are exempt from the establishment registration requirements (see § 207.10(b) (21 CFR 207.10(b)); as a result, such hospitals, clinics, and public health agencies are also exempt from the bar code requirements.

The rule also does not require hospitals to use or adopt bar code technology. Hospitals are free to decide whether to take advantage of the bar codes on human drug and biological products. Our legal authority, in this case, extends to the products and not to hospitals. Nevertheless, we advise hospitals and other potential bar code users that we are aware of electromagnetic interference (EMI) problems associated with the use of wireless technology products, such as cell phones, local area networks (LANs), and personal digital assistants (PDAs), in the vicinity of electrically-powered medical devices. EMI problems are a particular concern in health care facilities as well as home care settings. We caution that wireless bar code scanning technologies may present similar concerns about their electromagnetic compatibility (EMC) with other hospital equipment. We encourage hospitals and other potential bar code users to consider EMC with medical devices when developing their policies and implementing a bar code scanning system. Additional information about EMC with medical devices is available at

http://www.fda.gov/cdrh/emc

.

We recommend that interested parties gather information and conduct research about wireless bar code scanners (or other scanning or reading equipment) and their EMI potential on other medical devices. We also encourage voluntary standards development organizations, such as the Association for the Advancement of Medical Instrumentation, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), the American National Standards Institute (ANSI), and the International Electrotechnical Commission (IEC) to work with us toward the goal of coordinated policies, research, and standards development to ensure a base level of EMC in all health care facilities. This would include recommendations for safely deploying wireless technology in hospitals and health care facilities.

As for entities that repack or relabel drugs, if a repacker, relabeler, or private label distributor is subject to the establishment registration requirement at section 510 of the act, then that person would also be subject to the bar code requirements. We would expect that repacker, relabeler, or private label distributor to use its own NDC numbers on its products. In other words, a manufacturer, repacker, relabeler, or private label distributor must not use an NDC number that is not assigned to it. Use of another establishment's NDC number in the bar code would cause the product to be misbranded under section 502(a) of the act (21 U.S.C. 352(a)) because the drug's label would be misleading.

B. What Products Must Have a Bar Code? (§ 201.25(b))

Proposed § 201.25(b) would require bar codes on the labels of:

• All human prescription drug products, excluding samples;

• Biological products; and

• OTC drug products that are commonly used in hospitals and dispensed pursuant to an order.

We proposed to exclude prescription drug samples because most samples are given to patients at physicians' offices, and we did not believe that physicians or patients would have or be inclined to buy bar code scanners for their own use in the immediate future. We invited comment as to whether we should require bar codes on prescription drug samples and sought cost and benefit data associated with placing bar codes on such samples (see 68 FR 12500 at 12505 and 12529).

As for OTC drug products, the phrase “commonly used in hospitals” reflected our primary focus of helping to reduce the number of medication errors occurring in hospitals. We added the phrase, “dispensed pursuant to an order,” because we knew that some products that are regulated as OTC drug products, such as mouth rinses and toothpastes, are not likely to contribute to medication errors, and are not dispensed in hospitals pursuant to a physician's or health care professional's order. Thus, the phrase, “dispensed pursuant to an order,” was designed to capture those OTC drug products that are likely to contribute to medication errors. The preamble to the proposed rule invited comment as to whether there was a better way to describe the types of OTC drug products that should have a bar code (see 68 FR 12500 at 12506 and 12529).

The preamble to the March 2003 proposal also invited comment on whether any specific product or class of products should be exempt from the rule and the reasons for an exemption (see 68 FR 12500 at 12511 through 12512 and 12529).

1. Should Prescription Drug Samples Be Excluded From the Rule?

(Comment 3) Several comments said we should require bar codes on prescription drug samples. One comment stated that bar codes on samples would make it easier to monitor inventory or distribution to patients. Another comment said that prescription drug samples are “commonly dispensed in numerous hospital settings,” such as emergency departments, and that “the very nature of treatment and medication administration (in an emergency department) presents unique challenges for which bar coding would prove instrumental.” The comment also stated that JCAHO requires institutions to have policies and procedures in place to control drug samples and requires quick retrieval of recalled drugs, so hospitals must keep detailed records, “often including lot and expiration date, of drug samples dispensed to patients.” Another comment suggested that, rather than require bar codes on all prescription drug sample labels, we could simply require bar codes on the outer package because patients receive the entire package rather than a portion of a drug sample.

Other comments also wanted bar codes on prescription drug samples for reasons unrelated to medication errors. For example, one comment said that bar codes on prescription drug samples would reduce the amount of time spent tracking samples. Another comment said that bar codes could help pharmacists identify samples that patients present to them; the comment said that patients sometimes bring prescription drug samples to pharmacists because they wish to continue receiving the same drug. A third comment said clinicians might be confused if they had to follow one procedure for bar coded prescription drugs and a different procedure for nonbar coded prescription drug samples.

Conversely, several comments agreed with our decision to exclude prescription drug samples from the bar code requirement. The comments said there would be no benefit to bar coding such products, although one comment suggested that we conduct a study to see how prescription drug samples are used in institutional settings and to determine whether they should be the subject of a future rulemaking. Another comment agreed that bar coding prescription drug samples would not enhance patient safety, but said that one possible benefit would be that manufacturers could monitor disbursement of prescription drug samples.

Other comments suggested that bar codes on samples could be voluntary or noted that bar codes can fit easily on prescription drug samples because their packaging is often larger than unit-dose packaging (so that it is technologically feasible to put bar codes on prescription drug packaging) and that the Uniform Code Council (UCC) system requires bar codes on promotional products such as samples.

(Response) We decline to require bar codes on prescription drug samples. The comments did not offer any data to contradict our position that most prescription drug samples are dispensed by physicians in their offices and that physicians and patients will not be inclined to buy or use bar code scanners. We realize that bar codes could help with inventory control and help monitor distribution of samples, but those objectives have no bearing on medication errors or drug safety and are outside the scope of this rule.

Although one comment did claim that prescription drug samples are commonly dispensed in hospitals, particularly in emergency departments, we could not determine whether the comment meant to say that hospitals administer samples to patients or whether they simply provide samples to patients to take home. We also could not determine whether such practices are common in hospitals, but note that, under section 503(d) of the act (21 U.S.C. 353(d), hospitals may distribute prescription drug samples at the direction of a practitioner who is licensed to prescribe such drugs and who received such samples. (However, sections 301(t) (21 U.S.C. 331(t)) and 503(c) of the act prohibit the sale and purchase of drug samples.) If we assume that the comment pertained to distribution of samples in hospitals, then we reiterate that the physicians directing the distribution of the samples and the patients receiving such samples will not be inclined to buy or use bar code scanners. Consequently, requiring bar codes on prescription drug samples would have little benefit insofar as medication errors are concerned.

As for the possible use of bar codes in helping pharmacists identify drugs presented by patients, we note that part 206 (21 CFR part 206) requires imprinting on solid oral dosage forms. The code imprint was designed to help identify solid oral dosage forms, particularly in emergency situations, and to help consumers and health care professionals identify drugs (see 58 FR 47958, September 13, 1993; part 206). Thus, drug imprinting already exists to help emergency departments, and pharmacists can also use the imprint codes to help identify samples presented to them by patients.

As for the voluntary use of bar codes on prescription drug samples, we do not object to such use.

2. Which OTC Drug Products Must Have a Bar Code?

(Comment 4) Several comments focused on OTC drug products. One comment agreed that only OTC drug products commonly used in hospitals and dispensed pursuant to an order should be required to have bar codes. In contrast, an OTC drug firm stated that the rule's description of OTC drug products might be clear to hospitals, but was unclear to OTC drug manufacturers. The comment said that, instead of describing the OTC drug products that must have a bar code, we should list OTC drug products, categories of OTC drug products, and/or ingredients that do not require bar codes. The comment said such a list would give “clear direction” as to those OTC drug products that are subject to a bar code requirement.

Two other comments expressed similar views on listing OTC drugs. One comment said we should list categories of OTC drug products that would not have to have a bar code, whereas another comment said we should list the types of OTC drugs that would or should be subject to a bar code requirement.

(Response) We decline to revise the rule to describe the OTC drug products that would be subject to §§ 201.25 and 610.67 in terms of specific drugs, categories, or ingredients. The comments' suggestion that we list OTC drug products, categories, and/or ingredients would effectively force us to engage in case-by-case analyses to decide whether a particular OTC drug, category, and/or ingredient should or should not have a bar code and force us to engage in repeated rulemakings each time we wanted to modify the list. Additionally, parties that objected to listing a particular OTC drug product or class could attempt to challenge our decisions, creating an added burden on our resources. The result would be a cumbersome, time-consuming, resource-intensive, and inefficient administrative process that would detract from, rather than contribute to, efforts to improve patient safety. The original proposal's

formulation makes the distinction we are trying to draw and places the burden on manufacturers, repackers, relabelers, and private label distributors of OTC drug products to determine whether their products are commonly used in hospitals and dispensed under an order.

We have, however, re-worded § 201.25(a) to refer to “over-the-counter (OTC) drug products” and to use the shorter term of “OTC drug products” in the remainder of § 201.25. This change corrects an oversight in the proposed rule because it referred to “OTC drug products” without explaining what “OTC” meant.

(Comment 5) Proposed § 201.25(b) had explained that an OTC drug is “commonly used in hospitals” if it is “packaged for institutional use, labeled for institutional use, or marketed, promoted, or sold to hospitals.” One comment stated that the rule's reference to OTC drug products packaged and labeled for “institutional” use was confusing because the rule also referred to “hospitals.” Thus, the comment said we should clearly define the sites to which bar coded products must be distributed and define “hospital” and “institution.”

Two other comments suggested that we interpret “commonly used in hospitals” as “packaged for hospital use, labeled for hospital use, or marketed, promoted, or sold to hospitals.” Another comment said the interpretation of the phrase, “commonly used in hospitals,” should depend on a combination of two or more “indicators,” such as “packaging designed for institutional use, package labeling for institutional use, or marketing or promotion (including through sales catalogues) to hospitals.” The comment explained that our rule would “inadvertently sweep a far larger range of OTC medicines into the rule's coverage.” It also asked us to clarify that an OTC drug manufacturer would not be responsible for bar coding the drug if it was “marketed, promoted, or sold to hospitals” by someone else.

(Response) The proposed rule referred to “institutional use” because we knew that some OTC drug packages and labels state that the drug is “for institutional use” or “for institutional use only” (see 68 FR 12500 at 12505). We did not intend to imply that the rule would cover OTC drug products that were commonly used in “institutions” other than hospitals, and we have revised § 201.25(b) to replace “institutional use” with “hospital use.” However, we also have added the parenthetical phrase, “or uses similar terms” after “labeled for hospital use” to indicate that persons subject to the rule should adopt a common sense interpretation of § 201.25(b). For example, a manufacturer who labels an OTC drug “for institutional use only” and sells that OTC drug to hospitals should comply with the bar code requirement notwithstanding the fact that it labeled the drug “for institutional use only” instead of “for hospital use only.” In other words, we do not consider the OTC drug label's use of the word “institution” or its avoidance of the word “hospital” as being the determining factor in whether an OTC drug must comply with the bar code requirement.

As for defining what constitutes a “hospital,” the preamble to the proposed rule interpreted the word “hospital” as “a facility that provides medical, diagnostic, and treatment services that include physician, nursing, and other health services to inpatients and the specialized accommodation services required by inpatients” (see 68 FR 12500 at 12517, footnote 4 of table 2). We consider this interpretation to be sufficient for the final rule, but decline to codify this interpretation in the final rule. A codified interpretation of “hospital” would invite arguments as to whether a particular facility purchasing OTC drug products was or was not a “hospital,” whether the majority of purchasing institutions were or were not “hospitals,” and, as a result, would likely lead to further arguments about whether a particular OTC drug product sold to such facilities was subject to the bar code requirements. Engaging in such arguments would neither enhance patient safety, nor would it be an efficient use of our resources.

We also decline to interpret “commonly used in hospitals” as requiring two or more “indicators.” If we were to make the change as suggested by the comment, fewer OTC drug products would be subject to the bar code rule despite their use in hospitals and despite their potential for causing medication errors. For example, if we interpreted the rule to apply only to those OTC drug manufacturers who directly sold their products to hospitals, then an OTC drug manufacturer could avoid the bar code requirement simply by selling the OTC drug products, complete with labeling for “hospital use,” to wholesalers or middlemen for resale to hospitals. Similarly, if we were to adopt the comment's suggestion to change “packaged for institutional use” to “packaging designed for institutional use,” a firm could avoid the bar code requirement by making no distinction between its packages for retail sale and its packages for hospital use, because the package is arguably not “designed” for institutional use.

(Comment 6) Two comments stated that the phrase, “dispensed pursuant to an order,” is inappropriate because some institutions do not have orders provided by physicians or because some institutions allow nurses to request OTC drugs. Another comment suggested that we refer to OTC drugs that are “dispensed upon a prescription of a practitioner licensed by law to administer a drug;” the comment said this language would be clearer and eliminate any confusion as to what constitutes an “order.”

Several comments suggested that we refer to “non-prescription drugs used therapeutically pursuant to a prescriber's order,” although one comment used the phrase “pursuant to a rescuer's order.” The comments explained that the word “therapeutically” would exclude OTC drugs such as toothpastes and mouth rinses. Another comment suggested that the rule state that OTC drug products “are excluded from the bar coding requirements except for those OTC therapeutic drugs that are packaged for institutional use or specifically marketed for use in an institution for therapeutic purposes.”

(Response) The word “order,” in § 201.25(b), is not confined to any particular manner, document, or format for requesting a drug, nor is it confined to any particular type of health care professional. The phrase “dispensed pursuant to an order” should be interpreted as applying to an OTC drug that is to be administered to a patient as directed by a health care professional, regardless of whether he or she is a physician, nurse, or other professional. Consequently, we decline to revise the rule to refer to a “prescription of a practitioner licensed by law to administer a drug” because those terms would be more restrictive and would create more, rather than less, uncertainty over the rule's applicability to OTC drug products. For example, the word, “prescription” could be interpreted as requiring the practitioner to write a prescription for the OTC drug product before it could be administered to the patient. In contrast, an “order” could be an instruction written on a patient's medical chart, and could even be entered into the chart at the same time when the OTC drug is administered. As another example, the phrase, “practitioner licensed by law to administer a drug” could create uncertainty or disagreement as to whether a person was a “practitioner,” whether he or she was “licensed by

law,” and whether that license included the ability to “administer a drug.”

Similarly, we decline to revise the rule to refer to “non-prescription drugs used therapeutically pursuant to a prescriber's order.” There is no apparent distinction between a “non-prescription drug” and “OTC drug product,” and requiring such drugs to be used “therapeutically” could result in disagreements as to whether a particular use was “therapeutic.” For example, a person might interpret “therapeutic” as meaning that the OTC drug product must have curative or healing properties and distinguish such drugs from those whose purpose is prophylactic or intended to prevent disease. Another person might distinguish between OTC drug products that provide symptomatic relief and “therapeutic” OTC drug products by arguing that providing symptomatic relief does not address the underlying cause of a disease or condition and, therefore, is not “therapeutic.” We can avoid such potential arguments by not referring to “therapeutic” use.

We did not understand the comment that referred to a “rescuer's order” and did not believe the use of the word to be an appropriate substitute for an “order.”

(Comment 7) One comment suggested that the rule cover OTC drug products that are intended to be dispensed intact and in the original container as provided by the manufacturer, for use by inpatients. The comment explained that this description would cover various OTC drug products and also cover OTC drug products that are “comfort medications” that nurses can request without a physician's order.

(Response) We decline to adopt the comment's suggestion. The comment's suggested definition would encompass some OTC drug products, such as mouth rinses and toothpastes, that are not likely to contribute to medication errors but are nevertheless dispensed intact and in the original container to inpatients.

(Comment 8) One comment asked us to exclude OTC drug samples from the rule. The comment noted that we had excluded prescription drug samples because prescription drug samples are usually dispensed in physicians' offices and because we did not believe that physicians or patients would be inclined to buy or use bar code scanners. The comment claimed that the same rationale applied to OTC drug samples.

(Response) We decline to amend the rule as suggested by the comment because an amendment is unnecessary. The rule requires bar codes only for OTC drugs that are “commonly used in hospitals” and “dispensed pursuant to an order.” OTC drug samples would fall outside this bar code requirement because OTC drug samples are not “commonly used in hospitals” and are not “dispensed pursuant to an order.”

(Comment 9) One comment from an OTC drug manufacturer asked if the rule applied to all packages of a specific OTC drug. The comment explained that the firm uses a “modified open stock catalogue” that includes all retail and some hospital-specific OTC drug products and that hospitals can buy products from the catalogue. The comment asked if the rule would require the firm to put bar codes on all OTC drug products in the catalogue or whether the firm could put a bar code on one or more OTC drug products and still offer OTC drug products without bar codes in the same catalogue. The comment appeared to suggest that hospitals could then decide which version (i.e., bar coded vs. nonbar coded) to buy, and the OTC drug manufacturer would still be in compliance with the rule.

(Response) We interpret the comment as meaning that an OTC drug manufacturer may make two versions of the same OTC drug product. Both versions would use the same drug (in the same dosage form and strength); they would differ only with respect to the presence of a bar code on the product labels. Under such a scenario, we agree that the OTC drug manufacturer could, indeed, offer both the bar coded and nonbar coded versions of the OTC drug product in the same catalogue for hospital and retail sales, and we would consider the firm to be in compliance with the rule.

However, if the OTC drug manufacturer had several different versions of an OTC drug product that is commonly used in hospitals and dispensed under an order, and the OTC drug manufacturer decided to put the bar code only on one product, we might consider the OTC drug manufacturer to be in violation of the rule. To illustrate, assume that the OTC drug manufacturer makes three different dosages of a drug: A 50 milligram (mg) tablet, a 100 mg tablet, and a 200 mg tablet, and it sells all three products to hospitals. If the OTC drug manufacturer placed the bar code on the 50 mg tablet labels, but not on the 100 mg and 200 mg tablet labels, we would not consider the OTC drug manufacturer to be in compliance with the rule. In this scenario, we would expect the OTC drug manufacturer to put bar codes on the 100 mg and 200 mg versions of its product as well.

(Comment 10) One comment asked us to clarify that the phrases relating to hospital use and to institutional use pertained only to OTC drug products.

(Response) The comment understands the rule correctly. The rule applies to all prescription drug products (except for prescription drug samples, allergenic extracts, intrauterine contraceptive devices regulated as drugs, medical gases, radiopharmaceuticals, low-density polyethylene form fill and seal containers, drug products shipped by manufacturers, repackers, relabelers, and private label distributors directly to patients, and blood and blood components). We explain the reasons for excluding these drugs later in this section.

Insofar as OTC drug products are concerned, the rule applies to those OTC drugs that are commonly used in hospitals and dispensed under an order.

(Comment 11) One comment stated that we should require bar codes on Betadine. The comment did not explain why it singled out this particular OTC drug, but stated that including drugs such as Betadine would allow computerized databases to check for potential allergic reactions.

(Response) Betadine is an iodine solution and an OTC drug product that is commonly used in hospitals, but only some versions are dispensed under an order. Thus, under the final rule, only those versions that are both commonly used in hospitals and dispensed under an order would be subject to the bar code requirement.

While Betadine has the potential to cause allergic reactions, it would be impractical to revise this rule to impose a bar code requirement based on a drug's potential for allergic reactions. For example, an individual might be allergic to a color additive used in a drug; another individual might be allergic to a different drug component. Accounting for all potential allergens would require additional data to be encoded, and it may be difficult to accommodate more data on product labels.

3. Must Vaccines Have a Bar Code?

In the preamble to the March 2003 proposal, we invited comment on the risks and benefits of including vaccines in the rule (see 68 FR 12500 at 12505 and 12529). We explained that we were sensitive to possible adverse impacts on vaccine production and availability.

(Comment 12) Most comments, including comments submitted by individual vaccine manufacturers and a pharmaceutical industry trade association, said vaccines should be subject to a bar code requirement. Some

comments also stated that we should require lot number and expiration date information to be encoded for vaccines, too, because such information is needed for accurate medical records.

In contrast, several comments suggested that we consider carefully the impact of bar coding on vaccines. Although these comments did not recommend exempting vaccines from the rule, neither did they appear to fully support bar codes on vaccines. For example, one comment said that bar codes on vaccines will have minimal impact because most vaccines are administered in physicians' offices, and bar code scanners will not be readily available at those offices. Several comments, submitted by health professional societies or organizations, urged “caution,” stating that a bar code requirement could disrupt vaccine supplies and create a burden that exceeded the benefits of bar-coded vaccines. Another comment suggested that we create a separate regulatory process for vaccines and that we “engage” the vaccine industry to address data encoding issues.

(Response) Vaccines are subject to the final rule's bar code requirements by virtue of being prescription drugs. The comments did not show that the costs of bar coding vaccines exceeded the benefits, and we note that vaccine manufacturers themselves did not indicate that a bar code requirement would adversely affect vaccine production or supplies.

We decline, however, to require inclusion of lot number and expiration date information in a vaccine's bar code. As we stated in the preamble to the March 2003 proposal, the costs associated with encoding lot number and expiration date information appear to exceed the benefits (see 68 FR 12500 at 12507-12508). The comments did not provide evidence that would alter the cost-benefit analysis regarding lot number and expiration date information, so the final rule does not require such information in the bar code. Nevertheless, as we stated in the preamble to the March 2003 proposal, we will not object if firms voluntarily encode lot number and expiration date information (see 68 FR 12500 at 12508).

We also decline to establish a separate regulatory process for vaccines. We presented our concerns regarding bar codes and vaccines in a notice of a public meeting (see 67 FR 41360, June 18, 2002) and in the preamble to the March 2003 proposal (see 68 FR 12500 at 12504 and 12505). This rulemaking process, therefore, has given vaccine manufacturers and other interested parties ample notice and opportunity to participate on bar coding matters, so there is no public health need to create a separate regulatory process for vaccine bar codes.

4. What Other Types of Drugs Should Be Subject to a Bar Code Requirement?

a. Comments seeking to cover more drug products.

(Comment 13) Many comments stated that we should require bar codes on all human drugs. Health care professionals and hospitals submitted most of these comments, but the comments frequently gave no rationale for covering all human drugs or argued that failure to require bar codes on all human drugs would force hospitals to repack drugs and apply bar codes themselves, thereby increasing the risk that hospitals might apply the wrong bar code.

(Response) We decline to require bar codes on all human drugs. By focusing on prescription drugs and certain OTC drug products, the rule covers those drugs that are most likely to be involved in medication errors. We also note that the rule should reduce the need for hospitals to put bar codes on drugs.

If we required bar codes on all human drugs, then some drugs (such as samples) would have bar codes even though they are used outside the hospital setting and in situations where the patient is unlikely to have access to, or be willing to buy, scanning or reading equipment to read the bar code. Other drugs, such as certain toothpastes, mouth rinses, and even homeopathic drugs (which are “drugs” under section 201(g) of the act (21 U.S.C. 321(g)) would also have to have bar codes even though they are not associated with medication errors. Thus, bar coding all human drugs is unnecessary and would not contribute significantly to an overall improvement in patient safety.

(Comment 14) Two comments asked us to require bar codes on investigational new drugs or asked if investigational new drugs are subject to the rule.

(Response) Investigational new drugs have not been assigned NDC numbers because the number of investigational new drugs is constantly changing, and that constant change would exhaust the number of available NDC numbers quickly.

In addition, bar codes on investigational new drugs also could result in misleading information or compromise the clinical study. For example, if the clinical trial involved placebo controls, and the placebo used the same bar code as the investigational new drug, the bar code could mislead the computerized database into believing that the patient received an active ingredient rather than a placebo. If the placebo used a different bar code compared to the investigational new drug, the different bar code would reveal the difference between the placebo and the investigational new drug and introduce bias into the clinical study. Consequently, we decline to require bar codes on investigational new drugs.

b. Comments seeking to exclude specific drug products.

Although nearly all comments supported the rule, many comments sought to exempt or exclude particular products or classes of products from a bar code requirement or asked us to create a provision allowing case-by-case exemptions. In contrast, many comments, submitted mostly by hospitals and individuals, opposed any exemptions or opposed exemptions for specific products.

(Comment 15) Several comments asked us to exclude allergenic extracts from the rule. The comments argued that allergenic extracts encompass hundreds of different antigens, are sold directly to physicians, physician group practices, and clinics (or are not commonly used in hospitals) where bar code scanning equipment would not be used or where physicians and patients would have no incentive to buy bar code scanners, and that allergenic extracts do not always have NDC numbers. Another comment said that allergenic extracts are unique and tailored to each patient, so a manufacturer that had to comply with the bar code requirement would have to obtain NDC numbers for each extract, and this process would increase the likelihood of labeling errors. The comment also stated that a bar code requirement for allergenic extracts would be “unduly burdensome” and expensive; the comment estimated the cost of putting bar codes on allergenic extracts to be more than $120,000 for one firm alone.

(Response) We agree that allergenic extracts are used primarily in physicians' offices and that physicians and patients are not likely to buy or use bar code scanners. Consequently, we have excluded allergenic extracts from the final rule.

Because we have decided to exempt allergenic extracts, we do not find it necessary to address the comments' claims regarding burdens and costs.

(Comment 16) Some comments asked us to exempt products that are packaged together (“copackaged products”). One comment gave examples of products sold with titration packages or sold with different strengths or types in a package or carton that are used together. The comment explained that each

component could have its own NDC number, and asked what NDC number would be used for the copackaged product.

(Response) Even if two products are packaged together, and each product has its own NDC number, the copackaged product would have its own distinct NDC number. Thus, in the comment's example, the NDC number in the bar code would reflect the copackaged product and be distinct from the NDC numbers for the individual products, and so there is no reason to exclude copackaged products from the rule.

(Comment 17) Many comments asked us to exclude medical gases from the rule. The comments explained that compressed and liquid medical gases should be exempt from the rule because:

• Gas cylinders are located at a central supply point away from patients (so bar codes cannot be scanned easily);

• There is no easy way to affix a bar code at the quick-connect patient usage area that would discriminate between gas manufacturers;

• It is not technologically or financially feasible to have bar codes or to expect paramedics (who may be administering a medical gas) to use scanners;

• Cylinders and/or connectors are specific for gases;

• Cylinders are color-coded to reduce the potential for error;

• Gases, unlike other drugs, have dosages that vary per patient; and

• There are no known adverse events linked to medical gases.

Other comments asked us to exempt oxygen and medical gases for home use, stating that patients are unlikely to have bar code scanners in their homes, or that, for oxygen, the comment knew of no adverse reactions between oxygen and other drugs.

(Response) We agree that medical gases should be exempt from the bar code requirement. We do not, however, agree with all of the comments' arguments for exempting medical gases.

We are exempting medical gases from the bar code requirement because we conclude that bar codes on medical gases are not the best way to address medication errors associated with such drug products. We agree that, because medical gas cylinders are most frequently located at a central supply point away from patients, bar codes would not be scanned easily or in sufficiently close proximity to patients.

We also agree that there is no easy way to affix a bar code at the quick-connect patient usage area that would differentiate among gas manufacturers, and that the majority of medical gas cylinders are not patient-specific, but, rather, are used to administer medical gas to multiple patients. Because of these factors, which are unique to the administration of medical gases, we believe that bar codes are not the best way to address medication errors associated with medical gases.

We disagree with the arguments regarding the number of medical gas medication errors and the existence of adequate safeguards against such errors. The comments state that there have been very few medical gas medication errors. Low numbers of medication errors, alone, cannot justify an exemption. For example, if the type of medication error is serious (such as an error that results in death), then it would be difficult to justify an exemption on the grounds that a “low” number of deaths occur. Moreover, we have no basis to establish a threshold or baseline number of medication errors that would determine whether a particular drug had to comply with the bar code requirement. Even if we could establish such a threshold or baseline figure, that figure would be subject to challenge because health care professionals are not required to submit adverse event reports to us; in other words, the adverse event reporting system can signal the possible existence of a problem, but it cannot reliably predict the frequency with which such problems may occur.

We also disagree with the comments' claim that current provisions for the color-coding of high-pressure cylinders sufficiently protect against medication errors. At this time, color-coding of high-pressure cylinders is an industry recommendation rather than a requirement, so we cannot assume that all affected parties will choose to follow the recommendation. Additionally, injuries and deaths have resulted from administering medical gas from incorrectly colored high-pressure cylinders.

We also disagree with the comments' claim that medical gas containers have “unique connectors and valves” that decrease the potential for medication errors. Like color-coding, the use of unique connectors and valves is an industry recommendation and not a requirement. Our experience indicates that these connectors and valves can be and have been compromised such that incorrect gas has been administered, resulting in deaths and injuries.

Although we do not believe that bar codes are the best way to reduce medication errors in the administration of medical gases, we recognize the need for preventing such errors and have issued guidance on the matter, including a “Draft Guidance on the Current Good Manufacturing Practice for Medical Gases” (68 FR 24005, May 6, 2003), as well as a “Compressed Medical Gases Guideline” (February 1989). We intend to continue to evaluate medication errors associated with medical gases, and, as necessary, we may propose a regulation to reduce or prevent those errors.

(Comment 18) Two comments focused on contraceptives. One comment asked us to exempt oral contraceptives. The comment stated that it will be difficult to put bar codes on oral contraceptives because the tablets are contained in individual blister cells. The comment noted that oral contraceptives also have information regarding drug regimen compliance and placebos built into the package. The comment added that oral contraceptives are used outside the hospital setting.

The other comment asked us to exclude the Copper T intrauterine contraceptive and other intrauterine devices that are regulated as drugs. The comment asserted that these products are inserted into patients by physicians, are used outside hospital settings, and present no potential dosage error or administration error.

(Response) We decline to exclude oral contraceptives from the rule. Although oral contraceptives are contained in individual blister cells, those cells are usually placed in a single package with a single label, so the bar code would go on the label rather than on each individual blister cell. As for their use, we agree that oral contraceptives are used outside hospital settings, but do not believe that they are never used in hospitals.

As for the Copper T intrauterine contraceptive and other intrauterine products, we agree that such products, when used as specified, do not present medication error risks in the same manner as other prescription drug products, and we have excluded them from the rule. (These intrauterine contraceptive products are devices, but are regulated as drugs.) We also note that some hospitals may have additional procedures, such as requiring informed consent, before these intrauterine products are inserted, and those procedures may further reduce the risk of error.

(Comment 19) One comment asked us to exclude cosmetic-drug products which the comment characterized as not being subject to dosage limitations, such as anti-dandruff shampoo, deodorants, skin protectants, soaps, and sanitizers.

(Response) We decline to amend the rule as requested by the comment. Most products described by the comment would be OTC drug products and

probably would not be dispensed under an order. As a result, such products would not be subject to the bar code requirements. (It is also possible that some products, such as soaps, would be considered to be cosmetics rather than OTC drug products and would also be outside this rule.) We reiterate that only OTC drug products that are commonly used in hospitals and dispensed under an order are subject to the bar code requirements.

(Comment 20) Several comments sought an exemption for diluents. (A diluent is an agent, usually a liquid, that dilutes a substance (a drug, in this case) or makes it less potent or less irritating.) One comment claimed that diluents are not drugs, but acknowledged that some diluents do have NDC numbers. Another comment would not put bar codes on diluents that are packaged with another drug product because, the comment asserted, misidentification could occur after the diluent has been reconstituted with the other drug product. Another comment declared that bar codes on diluents should be voluntary and driven by the market rather than by regulation. Several other comments mentioned diluents or drug/diluent kits in a list of small products that, in the comments' view, warranted a waiver from the bar code requirement.

(Response) We decline to exclude diluents from the rule. Diluents are drugs under section 201(g)(1)(D) of the act if they are intended to be components of a drug. We are aware of medication errors involving diluents, so bar codes on diluents might help reduce or eliminate such errors. For example, bar codes on diluents could help prevent the following types of medication errors involving diluents:

• Use of the incorrect or improper diluent. Certain drug products are compatible with specific diluents, so using the incorrect diluent can compromise patient safety, especially if the incorrect diluent causes a precipitate to form that is not recognized when the drug is administered. Some precipitates are not recognizable by the human eye. An incorrect diluent can also be a problem if the patient has a particular medical condition (e.g., a diabetic patient receiving a diluent consisting of dextrose in water rather than normal saline). A bar code could alert a health care professional to the presence of an incorrect or improper diluent.

• Use of the incorrect amount of diluent. This can cause an incorrect final concentration of a drug, resulting in either an overdose or underdose of the prescribed drug. A bar code could verify that a diluent's amount was correct.

• Use of a diluent alone. We have reports where diluents were administered without the active ingredient. This error appears more likely to occur when the diluent and drug are removed from their package. In one case where a patient was supposed to receive an antibiotic oral suspension which was supplied as a lyophilized powder in a small bottle and milky white diluent in a larger bottle, the patient received the diluent only and not the antibiotic itself. A bar code could alert a health care professional that he or she is administering a diluent only.

• Incorrectly packaged or labeled diluents. There have been cases where a package was supposed to contain a diluent and active drug ingredient, but the product was incorrectly packaged so that it contained two vials of diluent. A bar code could alert a health care professional that the package contains only diluents.

If, as one comment indicated, a diluent does not have an NDC number, an NDC number should be obtained for that product. If a diluent is packaged with another drug, then, as we stated in our response to comment 16 of this document, the diluent, the drug, and the copackaged product would each have its own distinct bar code. Thus, if the diluent were separated from the drug in a copackaged product, the diluent would still have its own distinct bar code, and that bar code could be scanned.

(Comment 21) One comment asked that we exclude drug products that are shipped directly to patients. The comment gave an example of peritoneal dialysis solutions and said that an exclusion would be appropriate because patients would not be inclined to buy and use bar code scanners within their homes. The comment also claimed that the product it shipped is not typically used in hospitals.

(Response) We agree, in part, with the comment. If a prescription drug product is shipped directly from a manufacturer, repacker, relabeler, or private label distributor to a patient, then we will not require that product to be bar coded. We agree that patients will not have or be inclined to buy scanners for use within their homes.

However, similiar to our response to comment 9 in section II.B.2 of this document, if the same prescription drug product is marketed to hospitals, then we will expect that drug to have a bar code. In other words, to use the comment's example of a peritoneal dialysis solution, a manufacturer could produce two different versions of the same product; the version sold directly to patients would not have to have a bar code, but the version that is intended for sale to hospitals will be subject to the bar code requirement. By requiring the latter version to be bar coded, we will help prevent or reduce medication errors in the hospital.

(Comment 22) Several comments asked us to exclude nebules from the rule. (A nebule is a vial or container that holds a drug, usually in liquid form, before the drug is administered or dispensed in a device called a nebulizer.) The comments explained that we have been reluctant to approve nebules with a label due to concerns that labeling components could leach into the nebule and contaminate the drug. One comment added that, even if we were to approve a label on a nebule, it was unclear how a manufacturer could print the bar code.

Another comment asked whether the rule should apply to pharmaceuticals packaged with low-density polyethylene (LDPE) form fill and seal containers. The comment explained that placing a bar code on such products would present a drug stability issue. The comment said that if the rule applied to these products, then drug manufacturers would need additional time to comply with the rule because they would need to conduct stability tests.

(Response) The comments are correct that printing a bar code on such products could introduce volatile impurities into the drug (because the ink from the bar code could leach into the drug). We have provided guidance on LDPE container closure systems in “Guidance for Industry on Inhalation Drug Products Packaged in Semipermeable Container Closure Systems” (July 2002).

However, we also know that some products may be packaged with a foil overwrap. Consequently, we are granting a limited exemption. We will not require a bar code on LDPE form fill and seal containers that are not packaged with an overwrap, due to the potential leaching and contamination problem. (We do not need to mention nebules in this limited exemption because nebules are LDPE form fill and seal containers.) If the product is packaged with an overwrap, then we will expect the bar code to be displayed on the overwrap. A bar code on the foil overwrap (the secondary protective packaging) for individual or multiple LDPE units will not be in direct contact with the drug product, and the foil overwrap will prevent the ink and other impurities from contaminating the drug.

(Comment 23) One comment asked us to exclude prescription dental drugs from the rule. The comment claimed that prescription dental drugs are not used in hospitals and are applied by dentists in their offices or prescribed for home use, so bar codes would not be helpful.

(Response) We decline to exclude prescription dental drugs from the rule. We believe that prescription dental drugs are used in hospitals, so bar codes on prescription dental drugs would help prevent medication errors.

(Comment 24) One comment said we should exempt radionuclear drugs from the rule. The comment explained that the outside containers of radiopharmaceuticals are lead “pigs” that encase syringes and vials and are used to ship radioactive materials. The lead pigs are recycled, so any bar codes on the pigs would have to be removable. However, the comment claimed, a removable bar code on the lead pigs would require new labeling or shrink wrapping equipment, thus leading to a significant financial burden on nuclear pharmacies. The comment added that radiopharmaceuticals have a low “misadministration” rate of 30-40 reportable “events” annually compared against more than 14 million nuclear medicine procedures in 2002. The comment also claimed that a bar code would require nuclear pharmacies to amend their Nuclear Regulatory Commission (NRC) Agreement State licenses because the licensing authority would have to approve all labeling changes.

(Response) We agree that radiopharmaceuticals prepared at nuclear pharmacies should be exempt from the bar code requirement. The comment correctly stated that radiopharmaceuticals have a low misadministration rate. According to NRC data, the number of reportable medical misadministrations of radiopharmaceuticals has been in the range of 32 to 42 out of more than 14 million administrations per year for the last 5 years. The highest number of reportable misadministrations occurred in 1998, when there were 42 reportable events; this represented the highest total since the NRC began collecting data under the Government Performance and Results Act of 1992.

Low medication error rates are not, however, sufficient to warrant an exemption from the bar code requirement. Instead, our principal reason for exempting radiopharmaceuticals is that NRC regulations pertaining to the medical use of radiation byproducts render bar codes unnecessary for patient safety. For example, NRC regulations require, in many cases, that radiopharmaceuticals be administered under a written directive that ensures verification of a patient's identity before each administration (see 10 CFR 35.40(a) through (b), and 35.41(a) through (b)). We believe that NRC regulations pertaining to the use of radiation byproducts provide sufficient safeguards in preventing medication errors involving radiopharmaceuticals, and, because of this alternative regulatory program for these products, the benefits associated with a bar code would not justify the costs.

Because we have decided to exempt radiopharmaceuticals from the bar code requirement, we do not need to address the comment's other claims regarding labeling, packaging, and financial burdens.

(Comment 25) One comment, submitted by an OTC drug manufacturer, asked us to exempt its OTC drug products due to their “distinctive form” and “clear labeling.” The comment said that medication errors for its products (such as ready-to-use enemas, suppositories, and medicated topical creams) are “exceedingly rare.”

(Response) We decline to exclude OTC drug products that purport to have a “distinctive form” and “clear labeling.” A product's “distinctive form” and labeling do not preclude the possibility of drug interactions, wrong drug, wrong dose, wrong route of administration, or other types of medication errors.

We also decline to exclude OTC drug products, or even prescription drug products, from the rule even if their potential for medication errors is “exceedingly rare” (as the comment claimed). We have no basis to establish a threshold or baseline medication error rate that would determine whether a product should have a bar code, and even a “low” medication error rate could result in death or harm to patients. Furthermore, if we linked the bar code to a drug's medication error rate, the result could be that a drug might be bar coded at one time if its medication error rate exceeded the threshold, but not bar coded once the medication error rate fell below that threshold, and this could create confusion. For example, assume that the rule based the bar code requirement on a medication error rate of 5 percent. If Drug X had a medication error rate of 5.2 percent in Year A, it would be bar coded. If Drug X had a medication error rate of 4.9 percent in Year B, then it would not be bar coded. However, in all likelihood, in Year B, both bar coded and nonbar coded versions of Drug X would exist in the marketplace. If Drug X's medication error rate was 5.1 percent in Year C, the drug would, again, be subject to the bar code requirement. In such circumstances, the bar code would lose its value and reliability, insofar as medication errors are concerned, because hospitals would confront a constantly changing environment of drugs that have or lack bar codes, and hospitals would either not rely on such codes or lose confidence in the bar code system.

(Comment 26) One comment asked whether pharmacy-compounded prescription drugs would be subject to the bar code requirement.

(Response) As we noted in the response to comment 1 of this document, under section 510(g) of the act, pharmacies:

which maintain establishments in conformance with any applicable local laws regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon prescriptions of such practitioners licensed to administer such drugs or devices to patients under the care of such practitioners in the course of their professional practice, and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail

do not have to register their establishments or list their products with FDA. Thus, a pharmacy that compounds drugs in accordance with this provision would probably fall outside § 201.25(a) and compounded drugs made by that pharmacy would not have to bear a bar code.

We also note that pharmacy-compounded drugs do not have NDC numbers.

(Comment 27) Several comments focused on drugs in small vials or containers. Comments from several drug manufacturers and a trade association suggested that we exempt small vials and/or small containers from the rule, and several of these comments mentioned 5 milliliter (mL) vials, suppositories, small ophthalmic containers, prefilled syringes, and blister packs as examples of products that need an exemption. The comments stated that some vials or containers would be too small for a bar code. One comment suggested exempting vaccine unit-of-use containers if a manufacturer demonstrated an inability to apply a bar code due to space limitations.

In contrast, several comments strongly opposed exemptions for small vials and ampules. These comments explained that many of these products are high-

risk medications or that most injectable products come in small vials or ampules. Other comments said that liquid medications are more often linked to medication errors than solid dosage forms, so creating an exemption for vials and ampules would undermine the rule's effectiveness. Other comments opposed exemptions for small vials because the absence of a bar code would force hospitals to apply bar codes to the products themselves, and this would create the potential for labeling errors by the hospital.

One comment, submitted by the UCC, stated that, “No [UCC] pharmaceutical member has presented the UCC with a healthcare product too small for a [Reduced Space Symbology] symbol.” However, the UCC could not preclude the possibility that some small product could not be bar coded, although it did note that one firm had put bar codes on vials as small as 1 mL. The UCC comment also contained attachments describing how several pharmaceutical manufacturers (Abbott Laboratories, Baxter Healthcare Corp., Pfizer, Inc., and Aventis Behring) had decided to put bar codes on injectable pharmaceuticals, intravenous solutions, and other drug products.

(Response) We decline to exempt small vials or containers (including suppositories, prefilled syringes, and other small products for which comments sought exemptions). We agree that the risk of medication errors for these products cannot be ignored, and we also find the UCC's comments persuasive. If several pharmaceutical companies have already shown their ability to place a bar code on a 1 mL vial, we cannot justify a blanket exemption for comparatively larger products, such as 5 mL vials, and prefilled syringes.

Furthermore, we note that § 201.25(c) requires the bar code to appear on the drug's label. For some products described by the comments, the drug's label appears on an overwrap or packaging. Alternatively, it may be possible to modify the drug's immediate container to accommodate a label bearing a bar code.

c. Comments seeking a general exemption provision.

(Comment 28) In the preamble to the March 2003 proposal, we explained our reasons for not including a general exemption provision (see 68 FR 12500 at 12511 through 12512). We noted that industry-conducted pilot studies had placed reduced space symbology (RSS) bar codes on small vials and that those studies suggested that almost all products are capable of bearing a bar code. We also pointed out practical problems with an exemption provision, such as potential arguments as to whether it was “feasible” to affix a bar code and the resources that would be needed to deal with exemption requests (id.). Nevertheless, the preamble to the March 2003 proposal invited comment on whether we needed to create a waiver provision and how we could create a provision that would minimize the potential for misuse (see 68 FR 12500 at 12529 (question 8)).

Most comments opposed a general exemption or waiver provision. The comments said we would find ourselves expending resources to deal with exemption requests and that exemptions would cause more harm than good. Some comments opposed creating an exemption mechanism because they would prefer to have manufacturers repack their products or develop packaging that would support a bar code. Other comments noted that, if we exempt various products from the rule, hospitals will be forced to bar code those products themselves, and this could result in labeling errors and require hospitals to rely on two different data systems (one for bar codes with NDC numbers and another for drugs that the hospital has bar coded itself).

A few comments suggested that we create an exemption provision that would consider requests on a case-by-case basis or would be “limited.” The comments did not suggest how we might prevent misuse of an exemption provision. Another comment asked that we define an exemption review process.

(Response) Given the number of comments we received requesting an exemption for a specific product or class of products, the fact that the final rule contains certain categorical exemptions requested by some comments, and our inability to predict every future product or class of products for which an exemption might be justified, we felt it would be prudent to add a general exemption provision to the rule. Consequently, we have added a new § 201.25(d) which states that we may, on our own initiative or in response to a written request from a manufacturer, repacker, relabeler, or private label distributor, exempt a drug from the bar code requirement. The exemption request, under § 201.25(d)(1)(i), must document why compliance with the bar code requirement would adversely affect the drug's safety, effectiveness, purity, or potency or not be technologically feasible. The request must also explain why the problem cannot be reasonably remedied by measures such as package redesign or use of overwraps. Alternatively, under § 201.25(d)(1)(ii), the request must document why an alternative regulatory program or method of product use renders the bar code unnecessary for patient safety. For example, as explained earlier in our response to comment 24 of this document, we exempted radiopharmaceuticals from the bar code requirement because existing NRC regulations on the medical use of radiation byproducts render the bar code unnecessary for patient safety.

Section 201.25(d)(2) provides the address to which exemption requests should be sent. For human drug products, the request should be sent to the Office of New Drugs (HFD-020), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. For biological products, the request should be sent to the Office of Compliance and Biologics Quality (HFM-600), Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852.

We reiterate that we have created this general exemption provision to allow us to efficiently and justly address products or classes of products that we have not already considered. We emphasize that almost all drug products are capable of bearing, and should in fact bear, a bar code. We will not consider written requests that are based on other reasons (such as financial reasons, a claimed low rate of medication errors, or a claim that the product is somehow unique such that medication errors do not occur or rarely occur). Similarly, we will not entertain written requests seeking an exemption for a particular drug, class of drugs, or group of products when we have already refused to grant an exemption for the same drug, class of drugs, or group of products in this final rule. The general exemption provision is intended to be used in rare cases.

If we refuse to grant an exemption in response to a written request, our decision can be reviewed under our existing regulation at 21 CFR 10.75, “Internal agency review of decisions.”

5. Should Medical Devices Be Excluded From the Rule?

The preamble to the March 2003 proposal explained that we did not intend to issue any bar code requirement for medical devices at this time (see 68 FR 12500 at 12506). The preamble to the March 2003 proposal stated that devices present different issues compared to human drug and biological products and that we would continue to study whether to develop a proposed rule to require bar codes on

medical devices to prevent or reduce medication errors (id.).

(Comment 29) Two comments said we should reject the device industry's request for further study and require bar codes on devices. The comments said that implantable devices are made to detailed specifications and sometimes fail, so one could presume that a device manufacturer would recall defective devices. The comments added that bar codes on devices would help create patient records that could be easily searched so that hospitals could determine an appropriate course of action if a patient received an implantable device that was recalled.

Other comments argued that we should examine the benefits of bar code labeling on devices or that bar codes would be helpful on certain devices. For example, one comment said that patient safety would be further enhanced by applying bar codes to devices such as blood bags, filters, and apheresis kits.

Conversely, one comment agreed with our decision to omit devices from the rule. The comment said that devices present “unique” issues, such as product diversity, evolving coding technology, and unique product identification needs that are often negotiated between customers and device manufacturers. The comment recommended that we allow for voluntary use of Universal Product Numbers (UPNs) on devices in either the European Article Number/Uniform Code Council (EAN/UCC) or Health Industry Business Communications Council (HIBCC) standard. The comment explained that the UPN system is established and provides greater consistency with global identification trends compared to the NDC number.

(Response) We decline to include devices in the final rule. Unlike drugs, medical devices do not have a standardized, unique identifying system comparable to the NDC number. (There is a National Health Related Items Code (NHRIC) system for identifying and numbering marketed medical device packages, but participation in the NHRIC system is voluntary, and the database may contain out-of-date information due to industry acquisitions and mergers.) The absence of a standard, numerical identification system comparable to the NDC number is one of several issues that complicate efforts to put bar codes on medical devices for purposes of preventing or reducing medication errors.

We also note that permanently implantable devices are subject to our device tracking requirements at part 821 (21 CFR part 821), and those requirements can be quite detailed. For example, under § 821.25(a)(2)(iii), a device manufacturer must have a method of tracking each device that it distributes that enables the manufacturer to give FDA, within 10 working days of a request from FDA, information regarding the name, address, telephone number, and social security number (if available) of the patient receiving the device.

As for voluntary use of UPNs on medical devices and the use of EAN.UCC or HIBCC standards, we recognize that some devices already bear a bar code for reasons relating to purchasing or inventory control, and we have not objected to their use nor to the bar code standards used.

C. What Must the Bar Code Contain? (§ 201.25(c)(1))

1. Should We Require the Bar Code to Contain the NDC Number?

Proposed § 201.25(c)(1) would require the bar code to contain, at a minimum, the drug's NDC number. The NDC number identifies each drug product that is listed under section 510 of the act or section 351 of the PHS Act.

(Comment 30) Two comments claimed that their products, allergenic extracts, do not have NDC numbers. The comments stated, as part of a request to have allergenic extracts excluded from the rule, that FDA has allowed generic groupings for allergens under one NDC number. The comments added that they market nearly 200 to 300 allergens in four different package configurations each, so, if allergenic extracts had to carry bar codes, the firms would need from 800 to 1,200 new NDC numbers respectively, and this would have “enormous” implications for the firms and FDA.

(Response) As we stated in our response to comment 15 in section II.B.4.b of this document, we have excluded allergenic extracts from the rule. As a result, issues regarding NDC numbers for allergenic extracts are moot.

(Comment 31) Several comments focused on the NDC number itself. One comment said that the NDC number contains the necessary information for bar code purposes. However, several comments argued that OTC drug products should be allowed to use the Universal Product Code (UPC) number either instead of or in addition to the NDC number. Some comments said that OTC drug manufacturers would incur thousands of dollars of “unnecessary extra ‘new item’ costs” because different NDC numbers would be necessary for new, minor formulation changes to their drugs and create logistical complications for retailers (because retailers use the UPC codes). Two comments said that requiring OTC drug bar codes to contain the NDC number would increase the demand on NDC numbers, increase FDA's workload, or exhaust the number of available NDC numbers. One comment said it should be feasible for a database to handle both NDC and UPC numbers, whereas another comment said that allowing OTC drug products to continue using UPC numbers would make more NDC numbers available for other drug products and thus benefit the NDC number system.

Another comment supported the use of the NDC number with four extra digits. The comment said this 15-digit number, called “NDC Plus Four,” would identify individual doses and vital information about the drug, including, among other things, the drug's lot number, expiration date, and recall status.

Another comment asked us to change the NDC number so that it contained a drug's expiration date.

(Response) We decline to amend the rule as suggested by the comments. The UPC code does not necessarily identify a unique drug product. For example, if an OTC drug manufacturer made and sold a particular drug product, that drug product would have a UPC code, and it would also have a unique NDC number. If the OTC drug manufacturer reformulated the product (such as changing an ingredient), the manufacturer could use the same UPC code for the reformulated product, but the reformulated drug would have a different, unique NDC number. This could be significant to a patient's health if, for example, the reformulated product contained an ingredient that caused allergic reactions or drug interactions. Thus, requiring the use of NDC numbers, rather than UPC numbers, will help ensure that the drug is identified correctly.

Additionally, as we stated in the preamble to the March 2003 proposal (see 68 FR 12500 at 12507), we intend, through a separate rulemaking, to change the NDC number so that it becomes a unique identifying number for listed drugs. If we were to allow the use of other coding systems, such as UPC numbers that did not contain the drug's NDC number or an NDC number with additional digits, persons who wanted to decipher a drug's bar code would need to consult multiple information sources, and this would increase the likelihood that some information and databases might not be updated as frequently as others, that

some information might be unavailable, or that the information would be presented in different or incompatible ways. Although we understand the OTC drug industry's reservations about changing UPC codes to include NDC numbers because of a possible cost impact, § 201.25(b) only requires bar codes on OTC drug products that are dispensed under an order and are commonly used in hospitals. Furthermore, as we stated in our response to comment 9 of this document, we will allow OTC drug manufacturers to create bar coded and nonbar coded versions of the same OTC drug product; the bar coded versions, which would be intended for hospital sale and use, would carry the NDC number in the bar code. The versions intended for retail sale could continue to use the UPC code.

We also decline to revise the NDC number to include expiration dates or to add more digits to the NDC number. Revising the NDC number is outside the scope of this rule. Furthermore, expiration dates vary with each new batch or production run, so if we were to revise the NDC number to include expiration dates, we would quickly exhaust the number of available NDC numbers and be forced either to redefine the NDC number or develop an alternative system relatively quickly, and other databases that relied on the NDC number would also be forced to adapt or develop new systems themselves. Restructuring the NDC number in this manner would, therefore, be impractical and costly.

Similarly, adding more digits to the NDC number might be disruptive for those databases that already use or rely upon the NDC number. Those databases would either have to reconfigure themselves to handle 14-digit numbers (assuming all preexisting NDC numbers were modified to contain 14 digits) or reconfigure themselves to handle 10- and 14-digit NDC numbers (assuming that preexisting NDC numbers remained the same, but new drugs would receive a 14-digit number). Such reconfigurations could be expensive for those who maintain the databases and those who use them. A 14-digit number could also be either redundant or confusing in comparison to the Global Trade Item Number (GTIN). As the preamble to the March 2003 proposal mentioned, the GTIN is a 14-digit number which, when used in a bar code on drug products, contains the NDC number in conjunction with a code that identifies the product's packing level (see 68 FR 12500 at 12506).

(Comment 32) Two comments asked us to ensure that different parties use different NDC numbers. One comment said that the proposed rule failed to explain how repackers will distinguish a repacked product from the original manufacturer's package. The comment suggested that manufacturers use certain digits to signal the presence of an original manufacturer's package and that repackers use other digits to identify repackaged products. The comment said we should require repackers to have a manufacturer's identification number.

The other comment asked that we ensure that hospitals do not use the manufacturer's NDC codes when repacking a drug.

(Response) As we stated in our response to comment 2 of this document, if a repacker, relabeler, or private label distributor is subject to the establishment registration requirement at section 510 of the act, then that person is also subject to the bar code requirements and must use its own NDC numbers on its products. In other words, a manufacturer, repacker, relabeler, or private label distributor cannot and should not use an NDC number that is not assigned to it. Use of another establishment's NDC number in the bar code would cause the product to be misbranded under section 502(a) of the act because the drug's label would be misleading.

Hospitals, though, are exempt from the establishment registration requirements. Consequently, hospitals themselves are not subject to the bar code requirement, and we consider drug repacking and dispensing operations inside hospitals to be within the practice of pharmacy.

(Comment 33) Several comments addressed possible changes to the NDC number. The preamble to the proposed rule stated that we intended to redefine the NDC number through a proposed rule on drug establishment registration and listing (see 68 FR 12500 at 12506). Most comments opposed any redefinition of the NDC number. One comment said that redefining the NDC number would create confusion, possibly harm patients (although the comment did not explain how such harm would occur), and undermine the bar code rule. Other comments said that redefining the NDC number would be costly and disruptive to various databases that rely on or use NDC numbers. One comment said that we should not make a final bar code rule effective until the drug industry has had the opportunity to understand and comment on any changes to the NDC number. A different comment said we should consult various “stakeholders” before we make changes to the NDC number. Another comment said that we did not need to redefine the NDC number because the GTIN would provide “sufficient direction.”

(Response) As we stated in the preamble to the March 2003 proposal, we intend to revise our drug establishment registration and listing regulations to make the NDC number unique and more useful to informational databases, whether those databases are created to prevent medication errors, to obtain the latest information about a drug, or to track drug use and distribution. We are still preparing the proposed rule, and when we publish it in the

Federal Register

, we will invite comment on our proposed NDC number changes. Until we revise our drug establishment registration and listing regulations, the current requirements at § 207.35 continue to apply to the NDC number.

We also must point out that, even under a proposed drug establishment registration and listing rule, assuming there is no change in the product or packaging, we do not intend to replace currently-used NDC numbers. For existing NDC numbers, we would consider issuing a new number to an existing drug product only if there were two drugs that had the same NDC number.

(Comment 34) One comment criticized the NDC number, stating that it cannot tell whether the right dose is being administered because the actual dose may be a partial dose or multiple doses of the drug identified by the bar code. The comment said this reflected a technological limitation with NDC numbers, so the comment suggested that the computer systems used to document drug administration alert users and require manual intervention by health care professionals to verify doses.

(Response) The comment is correct that the NDC number may have certain limitations when different dosages are administered from a single package or when partial dosages are administered. For example, assume that a drug's package contains 20 tablets. The drug's NDC number will reflect the fact that the package contains 20 tablets. If the drug administered to the patient consists only of one tablet, then scanning the NDC number for the package alone will not show the correct dose given to the patient. The NDC number's principal value, in this scenario, is verifying that the correct drug in the correct dosage form is being administered. As another example, some drug product labels do not state pediatric dosages, so a physician might prescribe a partial dose for a pediatric patient. In this scenario, the NDC

number's principal value is verifying that the correct drug, in the correct dosage form, is being administered.

Regarding the comment's suggestions concerning computer systems, we agree that it could be helpful if a computerized database alerted health care professionals to check dosages given to patients. However, we do not intend to create, maintain, or regulate the databases that scanning equipment would consult to decode NDC numbers, so we advise parties to consider this issue when they develop computer systems associated with scanners to decode the NDC numbers.

2. Should the Bar Code Contain Lot Number and Expiration Date Information?

The March 2003 proposal would not require the bar code to contain the drug's lot number or expiration date. In the preamble to the March 2003 proposal, we explained that we were unable to show that the benefits associated with encoding lot number and expiration date information exceeded the costs, so we proposed to omit lot number and expiration date information from the bar code (see 68 FR 12500 at 12507). However, we also said that we would not object if drug manufacturers, repackers, relabelers, and private label distributors decided to encode lot number and expiration date information voluntarily (id. at 12508). We stated that industry representatives had suggested that they might add such information if a demand existed for it (id.), but we did not know whether hospitals and other health care facilities would be willing to pay more for drugs that had lot number and expiration date information encoded in the bar code. We invited comment on the costs and benefits associated with putting lot number and expiration date information in the bar code.

(Comment 35) Many comments urged us to require lot number and expiration date information in the bar code, but did not provide evidence to support their views. Instead, most comments declared that lot number and expiration date information would make it easier to identify recalled, contaminated, and expired drugs, would improve entries into medical records, or would provide greater patient safety. Other comments said we should phase-in a requirement to encode lot number and expiration date information over an extended time period, but did not discuss why a phased-in approach would alter the cost-benefit problem that we identified in the preamble to the proposed rule. Some comments would extend the rule's effective date to give firms more time to encode such information. Another comment urged firms to encode lot number and expiration date information, but only if the costs were not passed on to hospitals.

Other comments advanced different arguments for requiring lot number and expiration date information as part of a bar code. For example, one comment stated that the American Society of Hospital Pharmacists and others want lot number and expiration date information encoded, and so we should defer to them. Several comments said manufacturers should encode such information because they could do so at less cost compared to hospitals.

Several comments advocating the inclusion of lot number and expiration date information in a bar code argued that technology could encode such information. For example, one comment claimed that the information can be easily encoded using two-dimensional symbologies and noted that some manufacturers plan to encode such information voluntarily. Another comment noted that the GTIN, rather than the NDC number alone, could be used to provide additional patient safety information. Another comment declared that encoding lot number and expiration date information could be inexpensive because, the comment noted, firms already print the same information, in human-readable form, on packages.

In contrast, other comments supported our decision to omit lot number and expiration date information from the rule. Several comments conceded that the information could help trace recalled drugs and help with product inventory, but said that the information would not significantly reduce medication errors and that the costs of encoding the information would exceed the benefits. For example, one comment estimated that encoding lot number and expiration date information would cost $7,500 to $20,000 per manufacturer's line, excluding costs to verify the information. Several comments expressed concerns about the impact on production line speed. For example, one comment said that the online printing equipment that would be needed for encoding lot number and expiration date information is “highly ineffective and unreliable” at production speeds above 120 units per minute and that alternatives, such as preprinting labels, would present serious good manufacturing practice (GMP) concerns in verifying that the right label with the correct lot number and expiration date is used on the correct product. Another comment said that online printing and verification technology has not been demonstrated at production line speeds of 250 to 300 units per minute. A different comment listed various problems associated with online printing of lot number and expiration date information, such as adverse impacts on line speed and print quality, the need to develop unique bar codes for each packaging run, and limiting packaging options until printing and packaging technology becomes capable of supporting online product speeds and adequate print quality.

Another comment said we were correct to omit lot number and expiration date information from the rule because it would make bar coding more complex and perhaps discourage manufacturers from making unit-dose packages. The comment, along with other comments opposed to requiring lot numbers and expiration dates in a bar code, shared our view that the market would determine whether manufacturers and others encode lot number and expiration date information voluntarily.

One comment suggested that, if we decide to require lot number and expiration date information to be encoded, the information should only go on shipping cartons and not on individual packages because this would reduce the manufacturer's costs.

The comments also disagreed on how to interpret our recall data. The preamble to the proposed rule stated that we had examined the number of recalled drugs from fiscal year 1997 through fiscal year 2002 and that, while there were 1,230 recalls during that time period, there were few reports of adverse experiences associated with the administration of a recalled drug (see 68 FR 12500 at 12507). One comment said this data supported inclusion of lot number and expiration date information in the bar code because Class I recalls represent a reasonable probability that the use or exposure to the drug will cause serious adverse health consequences or death, and 97 of the 1,230 recalls were Class I recalls. In contrast, a comment that opposed inclusion of lot number and expiration date information in the bar code said the data were not sufficient to show any public health problem resulting from the administration of recalled or expired drugs.

(Response) The final rule does not require lot number or expiration date information to be included in the bar code. As we stated in the preamble to the March 2003 proposal, the data available to us do not indicate the magnitude of the public health problem associated with administering expired or recalled drugs, and we cannot

quantify the patient safety benefit associated with requiring lot number and expiration date information in the bar code (see 68 FR 12500 at 12507). The potential burden of encoding lot number and expiration date information appears to outweigh the potential benefit of encoding such information.

We emphasize that we do not dispute whether encoded lot number and expiration date information would be helpful in certain contexts that are unrelated to medication errors. We also do not dispute that the technology exists to encode such information or that certain firms have expressed their intent to encode such information. Nevertheless, while we recognize the strong desires expressed by some regarding lot number and expiration date information, we must also recognize the potential impact on manufacturers, repackers, relabelers, and private label distributors if we required them to encode lot number and expiration date information. The evidence before us indicates that the costs associated with encoding lot number and expiration date information, insofar as medication errors are concerned, exceed the benefits, so we decline to require such information as part of the bar code.

We reiterate that we will not prevent or prohibit firms from encoding lot number and expiration date information if they wish to do so, and we note that some drug manufacturers are encoding or intend to encode such information. We also remind hospitals and other potential bar code users that lot number and expiration date information may be encoded in two-dimensional or other technologies, so if they intend to purchase drug products with lot number and expiration date information encoded, they should consider carefully their scanning or reading equipment purchases (see 68 FR 12500 at 12507).

(Comment 36) Several comments would require other information to be encoded. For example, one comment said we should require the bar code to contain information regarding the drug's concentration, amount, and route of administration. The comment explained that information on the drug's concentration and amount could prevent errors involving concentration or overdose. It explained that information regarding the drug's route of administration could be helpful because, the comment claimed, some drugs are not to be administered intravenously or as major nerve anesthetics. Another comment focused on clotting factor products and wanted the bar code for these products to contain (among other things) the drug's brand name and number of units in a vial. The comment recognized that encoding the number of units in a vial might be difficult, but said that persons with hemophilia and other bleeding disorders often carry vials, but not package boxes that contained the vials, with them. It added that the additional information would provide better information about the product's efficacy, i.e., whether the patient achieved the expected hemostatic response given the units administered.

Several comments asked that we require the bar code to indicate the drug's waste disposal status under the Resource Conservation and Recovery Act (RCRA). The comments explained that medical personnel might not know that a particular drug, when it becomes a waste product, is regulated under RCRA. Some comments suggested that the drug's waste disposal status could be identified by adding another digit to the NDC number. One comment suggested that we coordinate with the Environmental Protection Agency to capture a drug's hazardous waste disposal status.

(Response) We decline to revise the rule as suggested by the comments. The NDC number, under a bar code system, is a link to information held in a database. For example, assume that the bar code contains the drug's NDC number. The scanner reading the bar code would transmit the NDC number to a computerized database, and that database could be designed to generate information regarding the drug's names, dose, concentration, route of administration, waste disposal status, etc. In other words, the information sought by the comments could be built into a database and does not have to be encoded in the bar code itself and does not require changes to the NDC number.

3. Can Information Be Omitted From the Label to Accommodate the Bar Code?

(Comment 37) Several comments suggested that we allow firms to exclude certain information from their labels so that they could affix a bar code. Some comments sought relief from the labeling requirements at § 201.10(i) (21 CFR 201.10(i)); that provision requires drug labels to contain the drug's proprietary name, established name (if one exists), an identifying lot or control number, and the manufacturer's, packer's, labeler's, or distributor's name. One comment suggested amending § 201.25(c), regarding the bar code's placement on a label, to state that any drug complying with the bar code requirement is exempt from § 201.10(i)(1)(iii) and (i)(1)(iv) (provisions regarding the identifying lot number or control number and manufacturer's, packer's, labeler's, or distributor's name) if the packaging size is such that the required information is not easily readable.

One comment sought clarification regarding a label requirement imposed by another Federal agency. The comment claimed that the Consumer Product Safety Commission (CPSC) has a regulation that requires drug products labeled for hospital use only to also bear a statement regarding use in households without young children.

Several comments focused on small labels. One comment stated that excluding “some” label information would help print high quality bar codes; the comment identified the manufacturer's or distributor's name and address as information that it would exclude from a label. Similarly, another comment would remove the manufacturer's name from the label because, the comment explained, the manufacturer's name is on the outer package and is part of the NDC number. Another comment stated that the only way to create room for a bar code on a small label would be to reduce font size, but the resulting print would be difficult to read.

(Response) We decline to amend the rule as suggested by the comments. In most cases, the information that the comments would remove from the label is required by Federal law, so we are unable to provide the relief sought by the comments. For example, section 502(b)(1) of the act considers a drug to be misbranded if it is in package form and its label does not contain “the name and place of business of the manufacturer, packer, or distributor.” Section 502(b) of the act does not authorize any exemptions from this requirement, so we cannot delete such information from the label simply to accommodate a bar code. Similarly, section 502(e)(1)(A)(i) of the act considers a drug to be misbranded if its label does not bear the drug's established name, so we cannot allow firms to exclude the drug's established name from the label. Additionally, section 351(a)(1)(B) of the PHS Act requires the package of a biological product to be marked with the product's proper name, the name, address, and applicable license number of the product's manufacturer, and the product's expiration date.

Furthermore, because the rule does not require lot number and expiration date information to be encoded, we decline to allow firms to remove the human-readable lot number and expiration date information from the label.

As for the comment seeking clarification of CPSC requirements, such matters are outside the scope of this rule and outside FDA's jurisdiction.

D. Does the Rule Require a Specific Type of Bar Code? (§ 201.25(c)(1))

1. Should the Rule Require Linear Bar Codes?

Proposed § 201.25(c)(1) would require the bar code to be a linear bar code that meets EAN/UCC standards. The preamble to the March 2003 proposal discussed, in some detail, how we decided to propose the use of linear bar codes and described the tension between trying to create a bar code requirement that would enable hospitals to buy scanning equipment with the confidence that their purchased equipment would not be rendered obsolete by new technology and trying to create a bar code requirement that offered some room for technological innovation (see 68 FR 12500 at 12508 through 12510). We also invited comment on whether we should consider the use of another symbol, standard, or technology, either with or in place of a linear bar code, the acceptance of that other symbol, standard, or technology among parties that would be subject to the rule, and the ability of hospitals to read or use other symbols, standards, or technologies (id. at 12510 and 12529).

(Comment 38) Many comments addressed the subject of linear bar codes. Several comments indicated the rule should require the use of linear bar codes because of their widespread use and because hospitals that are currently printing and scanning bar codes might be unable to upgrade their technology to support nonlinear technologies. One comment stated that our decision to require linear bar codes was “brilliant” and that our logic was “impeccable.” Another comment said that linear bar codes could be used as an initial requirement and that technology currently installed in most hospitals cannot be upgraded to support nonlinear technologies. The comment added that if we required nonlinear bar codes, hospitals could face significant costs, and those hospitals that had already implemented linear bar code systems would be penalized. Another comment said that many applications of currently-used linear bar code systems are appropriate for suppliers and end users. The comment, which was submitted by a supply company for two large, not-for-profit hospital alliances, added that it shared our concern that “technologies/standards not be so advanced that hospitals are then unable to read and scan the bar codes,” and it urged us to evaluate and promote new and emerging technologies “only as they become more readily available, and easily embraced by end users.”

Another comment said we should require the bar code to meet certain “attributes;” the comment explained that this would provide some flexibility (although it did not explain what the attributes would be or what that flexibility was) while still ensuring a minimum standard. The comment added that the standard should be one that does not require hospitals to spend significant amounts of money to replace scanning equipment that would otherwise be acceptable for use. Two comments submitted by drug manufacturers expressed a similar opinion, stating that we should allow firms to use any linear bar code symbology so that firms could pick the symbology that best fits their needs.

One comment agreed with our proposal to require linear bar codes, but asked whether this included multidimensional codes. The comment claimed that multidimensional codes are several thinly-stacked linear codes. It added that, while older bar code scanners might not be able to read multidimensional codes, we should not be concerned about older scanners because most hospitals would not have scanners (and therefore would not need upgrades) or that hospitals with older scanners could upgrade those scanners.

Most comments, however, argued against the use of linear bar codes or asked us to encompass other technologies or to eliminate any reference to linear bar codes in the final rule. Many comments claimed that the rule would discourage or inhibit technological innovation, although they differed as to their preferred alternatives to a linear bar code. For example, one comment said laws and regulations should encourage technological innovation, but did not explain why our particular rule had to do so. Comments opposed to a linear bar code requirement generally advocated the following alternatives:

• Two-dimensional symbologies, on the grounds that such symbologies can be used on small packages, require less space compared to linear bar codes, can encode more data than a linear bar code (although the comments usually did not explain why more data capacity was needed), or can be placed on solid dosage forms themselves. Some comments specifically mentioned DataMatrix as a recommended symbology, whereas others referred to symbols or systems created or marketed by the firm who submitted the comment or to symbols that would be marketed in addition to the two-dimensional symbology. Other comments suggested using two-dimensional symbologies in conjunction with linear bar codes, with the two-dimensional symbology encoding lot number and expiration date information.

• The EAN/UCC system generally, on the grounds that the EAN/UCC system is widely used for drug products, has defined data structures, is used internationally, and would be less expensive compared to a regulatory approach that imposed no standard. However, other comments opposed the EAN/UCC system, declaring it to be “obsolete,” or declaring that selecting the EAN/UCC would serve no purpose, would violate unspecified Federal laws, or would create a “monopoly” for the UCC. (We discuss comments on the EAN/UCC standard and HIBCC standards in more detail in comment 41 of this document.)

• Radio frequency identification chips. Some comments advocated the use of these chips and claimed that such chips could be an alternative to or used with the bar code and can be “highly effective” at identifying individuals and animals in a cost-effective manner. One comment noted that we had mentioned the comparatively high costs associated with radio frequency identification chips, but said we should not reject the chips on cost grounds alone. It said the pharmaceutical industry and health care providers should have the flexibility to choose identification techniques that are the most suited to a product or clinical setting. The comment added that if we required the use of a particular technology, we would create a conflict with our GMP principles because our GMP regulations do not require use of a particular piece of equipment, and we would be creating a disincentive for industry to develop more cost-effective identification systems.

• No standard or symbology at all. These comments advocated the use of “open” or “machine-readable” requirements so that market forces would decide which technologies would be used. One comment added that the use of nonlinear codes would make linear bar codes technologically obsolete by the time the final rule became effective. Another comment said we should require “automatic identification” instead of bar codes. Another comment suggested that manufacturers, repackers, and relabelers be allowed to customize symbols to meet customer needs, although the comment did agree that the NDC number should be present.

Comments were also divided on scanner technology. Most comments that addressed scanner technology declared scanner technology to be a “non-issue” because, they claimed, scanners can automatically discriminate between linear bar codes and can be reprogrammed or updated to read specific codes and even complex codes. One comment stated that the adoption rate of two-dimensional image readers is increasing and that such readers are becoming popular and less expensive. Others declared that high-resolution scanners can read both one- and two-dimensional symbologies and predicted that scanner manufacturers and suppliers would become very attentive to customer needs, so that scanner prices would fall. One comment said we should not be concerned about hospital costs at all or not consider such costs as limiting the industry's technological options; the comment argued that our consumer safety mandate precludes financial considerations, and claimed that the OTC drug industry “rises to the financial challenges presented by government regulations.” The comment noted that the rule does not require hospitals to buy scanners, so the comment said, “it seems irrational to tailor these requirements based upon what hospitals may or may not do to ensure the safety of their patients.”

In contrast, two comments indicated that technological limitations do exist. One comment agreed that scanners can read different symbologies, but said that printing technology, particularly with respect to variable information (such as lot number and expiration date), does not exist for high-speed, online printing. Another comment said that technology currently installed in most hospitals cannot be upgraded to support nonlinear symbologies; the comment said that if we required nonlinear bar codes, hospitals could incur significant costs, and those who had adopted bar code systems earlier would be “penalized.”

(Response) The comments reflect the same array of differing opinions that we encountered at the public meeting and described in the preamble to the March 2003 proposal (see 68 FR 12500 at 12508 and 12509). As we noted in the preamble to the March 2003 proposal, there are two principal, yet contradictory, themes. One theme advocates a specific technology or standard to promote uniformity and to create the conditions under which hospitals could invest confidently in their bar code scanning equipment. The other theme advocates innovation so that newer and perhaps better technologies might be adopted easily. Each theme has its advantages, disadvantages, and assumptions. For example, linear bar codes have the advantage of being a proven, established technology that is easily recognized and easily used. They may also be less expensive than newer, emerging technologies, and are capable of encoding the NDC number. However, linear bar codes have several disadvantages, too, as they offer limited opportunity for innovation and may take up more label space than newer technologies. They also may encode less data compared to other technologies. Thus, if we were to require more data to be encoded on the packaging or labeling for any other reason (such as to allow tracking and tracing of drug products through the drug distribution system), a linear bar code might prove too limiting.

In contrast, a position that advocates innovation, with or without identifying a particular technology, has the potential advantages of encoding more data in a smaller space and perhaps accommodating new technologies as they arise without any additional rulemaking. The disadvantages, however, would include the possibilities that new, emerging technologies may be unproven, not widely accepted, or present unknown risks. For example, current radio frequency identification chips may have less reliable read rates than a linear bar code, and we do not know whether the equipment needed to detect such chips will present EMI issues for other medical devices in the hospital environment. As another example, failure to prescribe a specific technology might deter hospitals and other potential users from buying scanning or reading equipment because there would be no assurance that drug manufacturers would use the same or compatible technologies. As yet another example, requiring “automatic identification” of the NDC number could lead some manufacturers to develop their own, exclusive identifiers, and individuals might not recognize those identifiers, particularly if those identifiers are very small, not widely used, or placed under the product's label. Thus, if we were to revise the rule to promote innovation, with or without identifying a particular technology, hospitals and other potential users might be reluctant to purchase scanning or reading equipment, and the rule's benefits would not be fully realized.

After reviewing the comments, we have decided to retain the linear bar code requirement, but will consider revising the rule to accommodate newer technologies as they become more mature and established. Our decision to retain the linear bar code requirement rests largely on the following considerations:

• Linear bar codes are an established and proven technology. They are widely used in many sectors, and we are unaware of any significant problems associated with linear bar codes and their scanners. In contrast, new technologies, such as the radio frequency identification chip, are still being developed or refined, and we do not know, at this time, whether or when those new technologies have or will have widespread acceptance or become standardized, or whether the equipment used to detect or read those new technologies will present any safety or regulatory issues. For example, we do not know whether the equipment needed to detect radio frequency identification chips will present EMI or EMC issues for other devices that are used inside hospitals.

• Linear bar codes are easily recognized and easily used or applied. Most individuals can identify a linear bar code quickly and can scan it without much training. For example, various grocery store chains have installed “self-scan” stations where consumers scan the bar codes on their purchases themselves; the consumers are able to do this with little or no training. In contrast, two-dimensional symbologies come in different shapes and sizes, and they can be smaller than linear bar codes. As a result, individuals might not recognize two-dimensional symbologies as quickly and might not even recognize them as encoding data. If the rule allowed any “automatic identification” technology, then the risk that individuals might not recognize the technology or lack the proper equipment to read that technology would increase.

• Although most comments opposed the proposed linear bar code requirement, they failed to agree on alternative technologies. For example, some comments supported two-dimensional codes, particularly DataMatrix, but others supported radio frequency identification chips. Some comments endorsed products that a specific company had created, while others suggested that we simply require “automatic identification” technology. We believe that if the rule is to result in any significant benefits, it must specify a technology so that hospitals and other interested parties can purchase the correct scanning or reading equipment. We do not agree with the comment that claimed it would be “irrational to tailor these requirements based upon what hospitals may or may

not do.” The rule's expected benefits are realized only if hospitals accept and use bar code technology. Therefore, we consider it prudent to consider what hospitals may or may not do when prescribing a regulation that is intended to benefit hospitals and their patients.

We also disagree that the rule prevents or otherwise hinders innovation. Automatic identification technologies are useful in other contexts, such as retail environments, and are used on many different consumer goods. In other words, the fact that the final rule requires the use of linear bar codes does not mean that all progress on other automatic identification technologies must stop, nor does it mean that innovative automatic identification technologies cannot be used on other products.

We recognize that other technologies may be able to encode more data in less space compared to linear bar codes. These arguments do not address the fact that this rule only requires firms to encode one piece of datum (the NDC number). A linear bar code is capable of encoding the 10-digit NDC number. Furthermore, such arguments do not address the principles of regulation that we must observe pursuant to Executive Order 12866; under section 1(b)(5), we are to design our regulations “in the most cost-effective manner to achieve the regulatory objective” and to consider “incentives for innovation, consistency, predictability, the costs of enforcement and compliance * * * flexibility, distributive impacts, and equity.” Applying that principle to this rule, we believe that a linear bar code is the most “cost-effective” device for encoding the NDC number particularly when, as the comments suggest, the alternative would be to specify no technology at all or encompass technologies whose data encoding capacities far exceed the information required. A linear bar code requirement offers consistency, predictability, and lower costs of enforcement and compliance compared to technologies whose acceptance and reliability may be uncertain, or compared to a requirement that offered no criteria upon which hospitals could rely.

We realize that, in October 2003, we issued a report entitled “FDA Counterfeit Drug Task Force Interim Report” (see Food and Drug Administration Press Release, “FDA Anti-Counterfeiting Task Force Interim Report Focuses on High-Tech Weapons and Other New Promising Measures,” dated October 2, 2003). This report discussed, among other things, anti-counterfeiting technologies, including “track and trace technologies.” The final rule does not affect the development or adoption of such “track and trace technologies.” Moreover, the final rule's underlying purpose (prevention of medication errors) is distinct from the purposes underlying anti-counterfeiting efforts (preventing the introduction of counterfeit drugs, facilitating identification of counterfeit drugs, minimizing consumer risk and exposure to counterfeit drugs, and avoidance of unnecessary costs on the prescription drug system). For example, in the medication error prevention context, the goal is to ensure that the right drug, in the right dose and right route of administration, is given to the right patient at the right time, so requiring a bar code on a unit-dose product is both necessary and appropriate, but information regarding the drug's origin (i.e., place of manufacture) is not essential. In contrast, for track and trace purposes, the goal is to ensure that individual products can be followed through the drug distribution system from the point of manufacture, but this goal does not necessarily extend down to the unit-dose package level.

Nevertheless, we reiterate that we will consider revising the rule to accommodate new technologies. As we explain in more detail in section II.I of this document, we expect compliance with the bar code requirement within 2 years after the final rule's effective date. At that time, we will begin examining other automatic identification technologies to determine whether we should amend the rule to allow the use of such technologies. We intend to conduct our examination in a public and transparent manner, with opportunity for public participation and comment. This could be done, for example, through a public meeting, a document inviting comment, an advance notice of proposed rulemaking, or other public forum. We will decide on the appropriate public forum at a future time.

Regarding the EAN/UCC system, the final rule allows the use of either EAN/UCC or HIBCC standards. We discuss the reasons behind this change at comment 41 of this document.

As for the comment concerning multidimensional codes, we note that there is disagreement whether certain symbologies are two-dimensional or simply a series of thin, one-dimensional codes stacked upon each other. Therefore, we cannot say, as a general matter, whether multidimensional codes are “linear bar codes” within this final rule because we cannot be sure that all parties share the same interpretation as to what constitutes a multidimensional code. Nevertheless, if a firm believes that a particular type of thin, one-dimensional codes that are stacked upon each other is still a “linear bar code” and intends to use that stacked code, that stacked code must be capable of being read clearly by scanning or reading equipment in the same manner as conventional linear bar codes to fall within § 201.25(c).

Finally, regarding one comment's claim that a linear bar code requirement would create a conflict with our GMP principles and will create a disincentive for industry development of other identification systems, we disagree. The linear bar code is not a manufacturing process; it is instead the visual representation of information. To use an analogy, we require labels to use the English language except where the article is to be distributed solely in the Commonwealth of Puerto Rico or in a U.S. Territory where the predominant language is not English (see 21 CFR 201.15(c)(1)). The English word is the visual representation of the information. If we had to accept any language on product labels (using the comment's GMP theory), then those using the product might not understand the information if they did not know the language used on the label. Furthermore, as we stated earlier in this response, the linear bar code requirement does not prevent anyone from developing innovative automatic identification technologies for any other industry for any other reason, and we will consider whether to accept other automatic identification technologies as they become more mature and accepted.

(Comment 39) One comment claimed it would be “legally indefensible” for hospitals to not choose two-dimensional systems if firms encoded lot number and expiration date information; the same comment also declared that some hospitals have their suppliers use two-dimensional codes so requiring linear bar codes would “force” those hospitals to “abandon” their systems because their suppliers would have to convert to linear bar codes.

(Response) We disagree with the comment. The only required piece of encoded data is the NDC number; hospitals are free to decide which scanning systems are best for them and are also free to decide whether to take advantage of any voluntarily-encoded lot number and expiration date information. We reiterate that we were unable to demonstrate that the benefits of encoding lot number and expiration date information would exceed the costs (see 68 FR 12500 at 12528 and 12529). Therefore, we disagree that it would be “legally indefensible” for hospitals to choose linear bar code scanners that are

perfectly capable of reading the NDC number contained in a linear bar code.

We also disagree that the final rule “forces” hospitals to abandon systems that they may have adopted before this rulemaking. If a two-dimensional scanning system is capable of reading both one- and two-dimensional symbologies, then the system should still be able to read the NDC number contained in the one-dimensional, linear bar code. We acknowledge, however, that if a hospital had insisted that its suppliers use only two-dimensional codes, the final rule's linear bar code requirement means that those suppliers must use a linear bar code to encode the NDC number. If the supplier wishes, it can encode lot number and expiration date information voluntarily using any symbology or automatic identification technology, so if the hospital insisted that the supplier use two-dimensional symbologies to encode lot number and expiration date information, the hospital's two-dimensional scanning system would still be useful.

(Comment 40) One comment asked whether “linear bar code” meant to include a specific symbology called “RSS-14 stacked.” The comment explained that RSS-14 stacked “is essentially the same thing as RSS-14, except that it is printed in two rows in order to make it narrower at the expense of height.” The comment said that a scanner can easily decode an RSS-14 stacked symbol, but added that, “I hope you get input from Scanner manufacturers on this point.”

(Response) The comment is correct that RSS-14 stacked is a variant of the RSS-14 linear bar code and that it consists of two rows of two segments each. A “separator pattern” is printed between the two rows to eliminate cross-row scanning errors.

We believe that RSS-14 stacked symbology can be read by linear bar code scanners, although the scanners would have to be programmed to read RSS-14 codes and, depending on the scanner, may require more time to read a stacked code. Thus, we would consider RSS-14 stacked to be a linear bar code within the rule.

(Comment 41) Some comments questioned or criticized the proposed rule's reference to UCC standards. One comment said that “standards” refers to the data structure and not to symbologies. The comment asked if we meant that the linear bar code had to be one used by the UCC and that the NDC number had to be in a UCC data format.

One comment, submitted by a medical device trade association, supported use of either the EAN.UCC or HIBCC standards. The comment explained that most medical device manufacturers who are voluntarily labeling their products use the UPN system, and the EAN.UCC and HIBCC standards comprise the UPN system. HIBCC also recommended that the final rule not rely solely on EAN.UCC standards; it acknowledged that EAN.UCC standards are “by far the most prevalent in pharmaceutical labeling,” but suggested that alphanumeric coding (which HIBCC standards use) “allows for literally-encoded information that is inherently safer” (than numeric coding alone).

HIBCC, as well as another comment, also stated that requiring EAN.UCC standards would create a monopolistic environment that might inhibit the development and implementation of technologies outside the EAN.UCC's purview. The other comment claimed that the UCC is not a standards body, has proprietary interests, provides sponsored bar codes to members as part of a variable annual fee, and that the linear bar codes that would be used on hospital patient identification bands are not EAN.UCC codes, so that there would be no benefit in selecting EAN.UCC standards. The comment protested that the EAN.UCC standard requirement would compel manufacturers to join the UCC even though adequate bar codes are available in the public domain, and declared that the rule would violate unnamed Federal laws by referring to EAN.UCC standards.

Another comment advocated use of both EAN.UCC and HIBCC standards. It suggested that this would encourage the adoption of automatic identification technologies as they develop, although the comment also recommended that linear bar codes be the initial technological requirement so that hospitals that have bar code systems are not disadvantaged.

(Response) Proposed § 201.25(c)(1)'s reference to UCC.EAN “standards” was intended to mean that the linear bar code had to be one that the UCC recognized and the data standard had to be in a UCC.EAN format (see 68 FR 12500 at 12509).

However, after considering the comments, we will interpret § 201.25(c)(1) as meaning that the linear bar code can be in any format, and the final rule gives firms the option of using EAN.UCC or HIBCC data standards. (We have revised the rule to refer to “EAN.UCC” standards, rather than “UCC/EAN” standards, in order to use the commonly-recognized abbreviation.) In other words, the manner in which the NDC number is encoded may be in an EAN.UCC or HIBCC format, and the manner in which the NDC number is visually presented must be a linear bar code. We have decided to give firms the option of using HIBCC data formats because HIBCC is a widely-recognized, nonprofit standards development organization whose standards, like EAN.UCC standards, are accredited by ANSI, and, as the comments suggested, allowing the use of either EAN.UCC or HIBCC standards may encourage further development and adoption of other automatic identification technologies. We also cannot preclude the possibility that some firms may prefer using alphanumeric code formats, which HIBCC uses, although we do not express any opinion as to whether alphanumeric codes are “safer” than numeric ones.

Allowing the use of HIBCC standards will also prevent the creation of the “monopolistic” environment that some comments feared. Although one comment claimed that the UCC is not a standards organization and implied that the UCC will benefit financially if we require bar codes to use EAN.UCC standards, our information is that the UCC is a not-for-profit standards organization.

We strongly recommend that manufacturers, repackers, relabelers, and private label distributors who are subject to the bar code requirement carefully consider their linear bar code symbology and standard choices. (The EAN.UCC or HIBCC standard may also determine the type of linear bar code symbology that is used.) The bar code's ability to affect medication error rates depends largely on the ability of hospitals to scan and interpret the data in the bar code. So, for example, choosing a commonly-used linear bar code symbology in a standard that scanners can easily read will have a greater impact on patient safety compared to a unique bar code symbology that few (if any) scanners are programmed to read.

2. Should the Rule Impose Any Conditions on the Bar Code?

Proposed § 201.25(c)(1)(i) and (c)(1)(ii) would require the bar code to be surrounded by sufficient blank space so that the bar code can be scanned correctly and require the bar code to remain intact under normal conditions of use. The preamble to the March 2003 proposal explained that some manufacturers had placed bar codes at locations where the bar codes are destroyed, damaged, or otherwise rendered useless (see 68 FR 12500 at 12510), so the proposal was intended to help ensure that the bar codes could be read correctly.

(Comment 42) One comment asked whether our reference to “blank space” referred to “quiet zones” in a bar code. A “quiet zone” in a bar code usually refers to a blank space that appears before the first bar and after the last bar.

(Response) Section 201.25(c)(1)(i)'s reference to “blank space” means that the linear bar code must be surrounded, on all four sides, by an area where no print occurs. This is slightly different from the “quiet zone” in a bar code because § 201.25(c)(1)(i)'s “blank space” would include areas that are above and below the bars.

We note, however, that we have previously indicated that we would not object if firms voluntarily encoded lot number and expiration date information (see 68 FR 12500 at 12508) and that such voluntarily-encoded information might appear in another machine-readable format with the linear bar code. For example, a firm might decide to use a composite code, where the NDC number is encoded in a linear bar code and the lot number and expiration date information is encoded in a two-dimensional code, with the two-dimensional component placed immediately above the linear bar code. If a firm elects to encode lot number and expiration date information voluntarily, and the voluntarily-encoded information is immediately adjacent to the required linear bar code, we will interpret the “blank space” requirement as applying to the entire composite code. In other words, we would not interpret the “blank space” requirement as preventing firms from using composite codes.

(Comment 43) One comment disagreed with proposed § 201.25(c)(1)(ii) insofar as it would require the bar code to remain intact under normal conditions of use. The comment said manufacturers should be allowed to print bar codes across perforations on blister packs as long as this did not affect the ability of the bar code to be scanned correctly. The comment said that printing the bar code across perforations would leave more space on the drug's label for other required information.

In contrast, another comment, submitted by a hospital, stated that the hospital's use of manufacturers' bar codes suggests that those codes sometimes fail to maintain their integrity. The comment said that linear lines become jagged, the markings degrade on the medium on which they are placed, or the bar code is placed in such a manner that it becomes unusable at the unit-dose level. The comment added that “it has been our experience that the bar code does not always agree with the written description of the product,” and it said that we should continue to require the bar code to remain intact under normal conditions of use, particularly with respect to unit-dose packages.

(Response) Section 201.25(c)(1)(ii) requires the bar code to remain intact under normal conditions of use. Our fundamental goal is to reduce or prevent medication errors, and that goal is best served when the bar code remains intact under normal conditions of use. As we stated in the preamble to the March 2003 proposal, partial or incomplete bar codes can provide misleading information or not be read at all by scanners (see 68 FR 12500 at 12510); these potential problems are avoided if the bar code remains intact under normal conditions of use.

We realize that label space can be limited due to other information that our statutes or regulations require to be on a drug's label, but there may be alternatives to printing the bar code across perforations. For example, the final rule does not require the bar code to appear on the same surface as other label information. Likewise, the final rule does not prevent a manufacturer, repacker, relabeler, or private label distributor from revising its packaging to accommodate more label information. Thus, there may be other approaches that would ensure that the bar code remains intact under normal conditions of use.

E. Where Does the Bar Code Go? (§ 201.25(c)(2))

Proposed § 201.25(c)(2) would have the bar code appear on the drug's label as defined by section 201(k) of the act. The preamble to the March 2003 proposal explained that section 201(k) of the act defines “label” as:

a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under authority of this Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper.

Thus, by proposing to require the bar code to be on the drug's label, proposed § 201.25(c)(2) would result in bar codes on the drug's immediate container label as well as the outside container or wrapper, unless the bar code is easily legible and machine-readable through the outside container or wrapper (see 68 FR 12500 at 12511).

(Comment 44) One comment asked that we require the bar code to “be oriented on the label in such a way as to promote visual reading of the drug, strength, etc. while scanning the bar code.” The comment explained that positioning the bar code in any other way would make users dependent on the scanning process instead of reading the drug's label. The comment said the only exception to its suggested placement restriction should be when the label does not support the bar code format, “with the burden on the manufacturer to justify the decision not to orient the label contents in this fashion.”

(Response) We decline to revise the rule as suggested by the comment. By not specifying how or where the bar code must appear, the rule gives firms considerable flexibility in designing their labels to include the bar code and any other information required by law or FDA regulations.

Although we recognize the comment's concern about relying too much on technology, we disagree with the comment's assumption that users will become dependent on the bar code and will stop reading drug labels. The human-readable information on a drug's label goes far beyond the drug's NDC number. For example, under § 201.100(d)(1), a drug's labeling, whether or not it is on or within a package from which the drug is to be dispensed, must contain adequate information for the drug's use, including any relevant warnings, hazards, contraindications, side effects, and precautions; the drug's NDC number will not provide such information. As another example, section 502(b)(1) of the act declares a drug to be misbranded if its label does not contain the name and place of business of the manufacturer, packer, or distributor, while section 502(e)(1)(A) declares a product to be misbranded if its label does not contain the drug's established name, quantity or proportion of each active ingredient. In short, the bar code, and the NDC number contained in the bar code, act more as a link between the drug, the patient, and the patient's drug regimen and do not act as a surrogate for the drug's label.

(Comment 45) One comment focused on products that are individually packaged in a tray or pouch and are considered sterile within the tray or pouch. The comment said we should allow the bar code to be placed on the tray or pouch because the drug is supposed to remain sterile and not be removed from the tray or pouch until the time the drug is administered.

(Response) We decline to revise the rule as suggested by the comment. By requiring the bar code to appear on the

product's “label,” § 201.25(c)(2) should result in a bar code on the immediate container label and the outer wrapper label. We are aware that, despite labeling instructions to the contrary, individuals might remove the outer wrapper and administer the drug product at a later time. Therefore, a bar code on the immediate container label may help prevent product mixups and medication errors that may occur when the drug product is removed from the outer wrapper and not used immediately.

As for the comment's drug sterility concern, we are not aware of any reason why including a bar code on the immediate container label as well as on the outer wrapper would adversely impact drug product sterility.

(Comment 46) Some comments focused on drug packaging. Some comments asked us to require bar codes on every unit-of-use package so that hospitals do not need to repack drugs. Several comments said we should require single dose packaging to make bar coding easier and accurate dosages more feasible. A different comment said that we should require manufacturers to have unit-dose packaging before they can market a drug. Other comments expressed concern that a bar code requirement might lead manufacturers to stop unit-dose or unit-of-use packaging or insisted that manufacturers use such packaging. Another comment asked us to require bar codes on “all packaging” as soon as possible, but a different comment agreed that we should require bar codes on unit-dose packages.

(Response) Regarding unit-of-use packages, the rule does require bar codes on such packages because § 201.25(c)(2) states that the bar code must appear on the drug's label. Section 201(k) of the act defines “label,” in part, as “a display of written, printed, or graphic matter upon the immediate container of any article.” Thus, because a unit-of-use package would be the immediate container for a drug, the unit-of-use package must bear a label and, under § 201.25(c)(2), have a bar code.

We decline to require manufacturers to use unit-dose or unit-of-use packaging. We recognize that concerns may exist over the rule's impact on such packaging, and we even raised the issue ourselves in our public meeting (see 67 FR 41360 at 41361). However, as we noted in the preamble to the March 2003 proposal, our industry contacts suggest that the costs associated with a bar code requirement “would not be great enough to significantly impact the market” and that “the expected reduction in hospital over-packaging could increase market demand for unit-dose products despite the cost difference” (see 68 FR 12500 at 12526). In other words, our industry contacts suggest that unit-of-use or unit-dose packaging decisions depend more on market demand than on bar code costs.

We also decline to require bar codes on “all packaging.” The preamble to the March 2003 proposal explained that requiring every package to bear a bar code would result in too many packages being bar coded regardless of the potential impact—or absence of impact—on medication errors. For example, we explained that requiring bar codes on every package would mean that a shipping container would have a bar code, yet no hospital would dispense a drug directly from a shipping container to a patient (see 68 FR 12500 at 12511). We maintain that requiring bar codes on all packages would not be helpful insofar as medication errors are concerned.

(Comment 47) One comment said that medicated creams and ointments can now be reduced from multidose tubes to single dose units and that some drugs have specific dosage requirements that further support the use of single dose packaging to mitigate dosing errors. The comment asked what is being done to convert packaging of semi-solids into “the needed single dose units.”

(Response) Issues regarding the production of unit-dose packaging, regardless of whether the drug is a liquid, cream, or solid, are outside the scope of this rule.

(Comment 48) One comment discussed how bar codes can be imprinted on pills. It described a system that uses images of the drug on medication schedules, prints bar codes on the drugs themselves, and uses two-dimensional bar codes with a “human recognizable icon or symbol” that identifies the “general type of pill.”

Another comment said we should consider technologies that allow one- or two-dimensional bar codes to be printed on color film coated tablets and other solid oral dosage forms. It added that covert marking systems could also be used to address drug counterfeiting concerns, and printing codes on the drugs themselves could reduce unit-dose packaging requirements.

(Response) We decline to allow the bar codes to be printed on tablets and other solid oral dosage forms. As we stated in our response to comment 3 in section II.B.1 of this document, 21 CFR part 206 requires imprinting on solid oral dosage forms. The imprint was designed to help identify solid oral dosage forms, particularly in emergency situations, and to help consumers and health care professionals identify drugs (see 58 FR 47948; 21 CFR part 206). If we allowed the bar code to be imprinted directly on a pill, the bar code might interfere with that drug's imprint and could force health care professionals and hospitals to consult two different databases (one on drug imprint codes and another on bar codes) to determine which drug they had before them.

Imprinting a bar code on a drug may also raise drug stability issues or affect a drug's dissolution rate. Imprinting bar codes on tablets has other practical limitations; for example, the same imprinting approach cannot be used for drugs that are in liquid, gaseous, or semi-solid form.

As for covert marking systems and counterfeiting concerns, such matters are outside the scope of this rule.

F. Must Blood and Blood Components Bear “Machine-Readable” Information? (§ 606.121(c)(13))

Current FDA regulations, at 21 CFR 606.121(c)(13), state that the container label for blood and blood components “may bear encoded information in the form of machine-readable symbols approved for use by the Director, Center for Biologics Evaluation and Research.” The proposed rule would amend § 606.121(c)(13) to require the use of “machine-readable information” in a format approved by the Director of the Center for Biologics Evaluation and Research (CBER) (the CBER Director). The CBER Director would review the machine-readable information technology to ensure that the minimum requirements are met regarding the accuracy of the required labeling information, spacing, and conditions of use.

Proposed § 606.121(c)(13) also would:

• Explain that all blood establishments that manufacture, process, repackage, or relabel blood or blood components intended for transfusion and regulated under the act or the PHS Act are subject to the machine-readable information requirement;

• State that blood and blood components intended for transfusion are subject to the machine-readable information requirement;

• Describe the minimum contents of the machine-readable information as a unique facility identifier, lot number relating to the donor, product code, and the donor's ABO blood group and Rh type;

• Specify that the machine-readable information must be unique to the blood or blood component, be surrounded by sufficient blank space so that the

machine-readable information can be read correctly, and remain intact under normal conditions of use; and

• State that the machine-readable information must appear on the label of the blood or blood component which is or can be transfused to a patient or from which the blood or blood component can be taken and transfused to a patient.

The proposal would not specify where the machine-readable information must appear on the label. As the preamble to the proposed rule explained, unlike the situation for other drugs, there is already substantial use of bar codes, notably ABC Codabar and ISBT 128, for blood and blood components (see 68 FR 12500 at 12512).

The preamble to the proposed rule invited comment on whether we should specify the use of ABC Codabar, ISBT 128, a different symbology or standard, or simply require the use of “machine-readable information” approved by the CBER Director (id.). We also invited comment on whether a “machine-readable information” approach was feasible or whether we should require the use of EAN.UCC

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