Labeling Operations and Controls

Labels are an integral part of the drug product packaging process and the marketing of the final drug product. They provide essential information regarding the contents of the drug product, such as strength, dosage, medical claims, and drug warnings. According to the United States Food and Drug Administration (FDA), drug products that are mislabeled can pose a threat to public health, cause product recalls, and seriously damage the image of the drug manufacturer.

As a result, labels are designed, produced, and controlled to meet good manufacturing practices (GMP) that ensure the identity and quality of the product. Additionally, it is the ultimate responsibility of the drug manufacturer to ensure that the label integrity is never compromised (print quality, label adhesion, and so on) during the life span of the drug product, from distribution to its intended use. The requirements for label control and packaging components are becoming increasingly stringent. To address these requirements, drug manufacturers, as well as label manufacturers, are moving toward electronic verification of the printed labels, and improved inventory control systems that allow tracking using bar codes printed on each label.

In February 2004, FDA released a rule requiring bar codes on human drugs and biologic products. By implementing bar code tracking, FDA hopes to reduce the number of medication errors, thus ensuring that health professionals provide patients with the right drug and proper dosage. The rule also applies to establishments that handle blood components that will be used for transfusions. According to FDA, this new rule will help prevent nearly 500,000 adverse events and transfusion errors and concurrently will help save US$93 billion in healthcare costs over 20 years.

FDA’s final rule requires the use of a linear bar code to code the National Drug Code (NDC) on most prescription drug products and certain over-the-counter (OTC) drug products.


In general, the labels destined for the packaging operation of the drug product are printed by a vendor that has been certified by the drug manufacturer. To ensure that the correct labels are received, each shipment of labels that arrives at the manufacturing site is subjected to several steps:

The receiving department at the drug manufacture receives the labels. Records must be maintained for each shipment of labels received from the vendor (printer)

A quarantine area or controlled area is designated to store the received labels while incoming inspection is done by the quality unit (QU).

The labels are sampled for inspection against defined reject criteria (acceptable quality level [AQL] inspection method).

The QU releases or rejects the labels. If the label is released, an identification or lot number typically is assigned.

The labels are maintained in a secured and controlled area while awaiting release for packaging use. Access to this controlled area should be granted only to a few individuals. Additionally, labels destined for different products or different strengths of the same product need to be stored separately to avoid potential errors.


GMP guidelines are in place to ensure that not only the type of label but also its quantity are controlled strictly when being issued for packaging of the drug product. The manufacturers of the drug must have standard operating procedures (SOPs) that detail the steps to follow when labels are issued to manufacturing.

Label specimen verification is required to ensure that the current version of the label is being documented on the drug product batch record. Label verification is required to guarantee that all labels to be used match the identity of the label template (specimen) specified in the drug product batch record. The label verification step implies a 100 percent inspection of all labels that will be installed in the labeling equipment. Each label is counted and verified either by manual methods or by electronic verification. Several methods of electronic verification currently are used by drug manufacturers, and they typically use an electronic visual inspection of each label by means of a camera that compares a photograph of each label with the approved label specimen.

SOPs specify how many labels will be issued against the planned number of containers to be labeled. Furthermore, the completed batch records must show comparisons between the number of labels that were issued to manufacturing, the number of labels used, and the number of labels not used during the operation. An investigation is initiated and completed if any discrepancies are found during the label reconciliation process.

Unused labels can be returned to the controlled storage area if they have not been printed with the drug product batch number; however, most companies have procedures requiring that unused labels be destroyed in an effort to prevent label errors.


Label control is extremely important for all drug products, as labeling mix-ups and printing errors continue to be a major source of product recalls. Drug manufacturers need to ensure that the information printed on the labels does not degrade over time. Thus, it becomes fundamental that the inks used for label manufacturing are light resistant, do not smear, and do not leave traces of odor. Additionally, the printing must conform to the approved label specimen (for example, uniformity, art specification).

Another factor that is controlled by drug manufacturers is the labeling operation. Just as batch records are required to document label issuance operations, they are also required for recording key aspects of the actual labeling operation (Figure 54.1).


The guidelines for GMP require that the drug expiration date is noted on the label. Moreover, if the drug product is to be reconstituted at the time of use, the label must include the expiration dates for the reconstituted and un-reconstituted drug product.


Failure to ensure that strict control is exercised over labeling issued for use in drug product labeling operations as required by 21 CFR § 211.125(a). Your firm does not exercise adequate controls over the labeling issuance and labeling operation of the drug products being handled at your facility. Your firm’s personnel were not aware of the labeling requirements set forth by the abovementioned regulation.

Failure to ensure that written procedures are designed and followed to assure that correct labels, labeling, and packaging materials are used for drug products as required by 21 CFR § 211.130. Your firm had not established or implemented procedures to assure that correct labels were applied to your . . . products.

Failure to control labeling operations to prevent labeling mix-ups and to document the labeling used in the DHR as required by 21 CFR § 820.120(d). For example,

implant  .  .  .  was  manufactured and released on  10/28/08  with  labeling  that  indicated that the device was non-sterile. However, this implant was returned to . .

. for sterilization and the sterilization record found in the device history record (DHR) for this implant shows that the implant was sterilized on 11/5–6/07. The sterilization record was signed off on 11/8/07, and the product was shipped on 11/18/07. The only label included with this DHR indicates that the product was labeled as nonsterile.

Other Examples of FDA Warning Letters

Your product labeling specifies a 10-day use limit under the “Warnings” heading in the “Drug Facts” panel (that is, “Stop use and ask a doctor if . . . pain gets worse or lasts more than 10 days”) but this warning appears only within the Drug Facts panel of the retail package. Its placement within the perimeter of the Drug Facts panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling “For calcium, adults and children 12 years and over, take up to 4 caplets per day . . . ,” without any limitation on duration indicated.

Your product labeling warns against use by children and teens, to prevent Reye’s syndrome (that is, “Warning—Reye’s syndrome: Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye’s syndrome, a rare but serious illness reported to be associated with aspirin.”), but this warning appears only within the “Drug Facts” panel of the retail package. Its placement within the perimeter of the Drug Facts panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling “For calcium, adults and children 12 years and over, take up to 4 caplets per day . . . ,” without any warning that there are circumstances where it is not appropriate for children and teenagers to take the product.