Which of the following would be considered a serious labeling issue for a drug?

A serious labeling issue for a drug would indeed be a missing expiration date. The expiration date is essential for ensuring that the medication is safe and effective for use. It indicates the date until which the manufacturer can guarantee the full potency and safety of the drug. Administering a medication beyond its expiration date could lead to ineffective treatment or potential harm to the patient.

In contrast, while the other factors, such as the color of the container, the shape of the tablets, and the size of the box, may have implications for brand identification or patient familiarity, they do not directly impact the safety and effectiveness of the medication itself in the same critical way that a missing expiration date does. Therefore, these factors are less significant in terms of labeling compliance and patient safety concerns.