FDA Publishes Guidance For Biopharma Container Labels & Carton Labeling Design
By Mark Durivage, Quality Systems Compliance LLC
On May 18, 2022, the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) released Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors Guidance for Industry. The purpose of this guidance is to minimize medication errors and protect the end user. The FDA defines the end user as the patient, the patient’s caregiver, the physician, the nurse, the pharmacist, the pharmacy technician, and other individuals who are involved in the routine procurement, stocking, storage, selection, dispensing, preparation, and administration of medications. This guidance focuses on safety aspects of the container label and carton labeling design and provides a set of principles and recommendations for ensuring that critical elements of a product’s container label and carton labeling are designed to promote safe dispensing, administration, and utilization of the product by the end user.
The scope of this guidance includes prescription drug products marketed under an approved new drug application or abbreviated new drug application, prescription drugs marketed without an approved application, and biological products marketed under an approved biologics license application. This guidance does not directly apply to over-the-counter drug products, compounded products, marketed prescription products used in clinical or bioequivalence studies, or investigational products; however, the principles may still be useful to prevent improper use or errors.
The Institute of Medicine (IOM) published a report in 2006 titled Preventing Medication Errors, which cited labeling and packaging issues as the cause of 33 percent of medication errors and 30 percent of fatalities were due to product naming, labeling, and packaging issues. The report emphasized that product naming, labeling, and packaging should be designed for the end user — the provider in the clinical environment and/or the consumer.
For the purpose of consistency and clarity in this article, the FDA defines a label as “a display of written, printed, or graphic matter upon the immediate container of any article.” If any word, statement, or other information is required by the FD&C Act to appear on the label, it must appear on the outside container or wrapper, if there is one, or be “easily legible through the outside container or wrapper.” labeling is defined as all labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers or accompanying such article.”
General Labeling Considerations
The format and content of prescription drug and biological product labels and labeling must comply with 21 CFR Part 201, Labeling and 21 CFR Part 610, General Biological Products Standards and conform to United States Pharmacopeia (USP) labeling requirements (USP General Chapters numbered below 1,000 are requirements if referenced in the drug’s USP/NF monograph) to avoid issues with 21 U.S. Code § 352 - Misbranded drugs and devices.
Robust risk management activities during the design and development of labels and labeling for a product’s container and carton are crucial to prevent medication errors by the end user (see Safety Considerations for Product Design to Minimize Medication Errors). The FDA’s recent guidance provides principles and recommendations for ensuring that critical elements of a product’s container label and carton labeling are designed to promote safe dispensing, administration, and use of the product. The items described in the guidance are intended to support flexibility where appropriate. To that end, the FDA strongly encourages sponsors to discuss product-specific design questions with FDA via appropriate regulatory pathways as early as feasible in the product development timeline.
General labeling considerations and awareness provided in the guidance include:
- poor design of product container labels and carton labeling can obscure critical safety information;
- risk assessments performed during the design stage can reduce the risk of medication errors;
- critical product information should appear on the principal display panel;
- container labels and carton labeling should be legible, readable, and understandable;
- avoid using error-prone abbreviations, acronyms, symbols, look-alike container labels, and carton labeling; and
- ensure consistency between the container label and carton labeling and other approved labeling.
The principal display panel (PDP) is the panel of a container label or carton labeling that is most likely to be displayed to, presented to, shown to, or examined by the end user and contains the information allowing for proper identification of the product. The FDA recommends the PDP include the following critical information:
- Proprietary name if there is one
- Established name or proper name
- Dosage form
- Product strength
- Route(s) of administration
- Warnings (if any) or cautionary statements (if any)
- Controlled substance schedule if the product is a controlled substance
To ensure the container labels and carton labeling are legible, readable, and understandable, the FDA recommends using “sufficiently large container labels or unique packaging to accommodate all critical and required information on the immediate product container label.”
Container labels and carton labeling should use fonts that are not lightweight or condensed. The National Patient Safety Agency’s reports, Information Design for Patient Safety: A Guide to the Graphic Design of Medication Packaging and Design for Patient Safety: A Guide to the Labelling and Packaging of Injectable Medicines, recommend using 12-point sans serif to improve readability.
Using similar colors for the container labels and carton labeling of multiple products across a company’s product line or within a line of related products is a commonly cited contributing factor in reported medication errors. Individual users’ abilities to perceive colors vary greatly, so relying on color to identify a product may cause users to not read the label. Colors can also be problematic in that there are a limited number of discernible colors and colors can look different under certain lighting conditions, such as natural outdoor light or indoors under florescent or LED lighting. The color contrast between the text and the container label or carton labeling background color on top of which text is placed should be chosen to afford adequate legibility of the text and to avoid color combinations that do not afford adequate legibility of text.
For container labels or carton labeling that are crowded, the text size and prominence are generally decreased, and important information may be difficult to read or easily overlooked. To reduce information crowding and visual clutter, the FDA recommends placing noncritical information on a side or back panel of the container label and carton labeling, rather than on the PDP, or placing it, as appropriate, in the package insert (PI).
When space permits on the carton labeling, changes to marketed products, such as new strength(s), formulation, certain inactive ingredients, or product appearance, can be communicated to health practitioners on the container label.
Certain abbreviations, acronyms, and symbols should not be used on container labels or carton labeling because they are frequently misinterpreted and can lead to medication errors that result in patient harm. The Institute for Safe Medication Practices (ISMP) provides a comprehensive list of Error-Prone Abbreviations, Symbols, and Dose Designations which should be avoided to prevent harmful or potentially harmful medication errors.
Container labels and carton labeling that look alike frequently contribute to product selection errors, leading to the dispensing and administration of the wrong drug, wrong strength, and/or wrong dose. The opportunity for look-alike product confusion is increased when products with similar-looking container labels or carton labeling are stored in close proximity to one another.
Corporate trade dress is a term describing the manner in which a company packages, wraps, and labels a drug or biologic product, including the use of color schemes, sizes, designs, and shapes and the placement of words or graphics on a container label and/or carton labeling – in other words, branding. To reduce look-alike container labels and carton labeling, corporate trade dress should be designed to provide information on the label that is legible, readable, and not subject to confusion and that ensures the end user is able to distinguish between different medications or different strengths of the same medication and distinguish the container labels and carton labeling of multiple products.
Color coding may be appropriate in certain circumstances, including drug product strengths, where the colors of the strengths are universally color-coded across all manufacturers. The FDA suggests other methods of distinguishing container labels and the carton labeling of multiple products, such as bolding, boxing, and varying fonts.
Double-sided container labels and carton labeling can help prevent medication errors. When printing on the front and back panels, critical information should be repeated on each side.
Quick Response (QR) codes are not required to be included on the product labeling and do not contain the required information. The FDA has not established a formal position on the use of QR codes and will review proposals to include such codes on a case-by-case basis.
Product sample units must bear labels that clearly denote their status as drug samples, should include the expiration date and product strength, and provide space on the label so the provider of the drug sample can write or affix a label with the patient’s name and specific instructions for use.
Container Label & Carton Labeling Considerations For Specific Product Types
Blister packs are available in various configurations. When a blister cell has a label, the bar code and other required or critical information should appear over each blister cell so that this important information remains available to the end user up to the point at which the last dose is removed. The PDP and other panels of the blister carton labeling should describe the milligram amount of drug per single unit to eliminate confusion on how much product is contained in a single unit compared to the total contents of the entire blister pack.
Due to the reflective nature of foil, the text on the pack may not be readily legible. Where possible, a nonreflective material should be used. Blister packaging configuration should be intuitive for the dosage and administration of the drug product and the intended patient population.
Injectable drug products
Vials for injectable drug products often include stoppers that are connected to the vials by an overseal that protects the stopper. The location of ferrules on medication vials provides crucial information to the healthcare provider and should be limited to important safety messages critical for the prevention of imminent, life-threatening situations. For example, a black cap overseal and a black ferrule or a black band or series of bands above the constriction on an ampule are used only for Potassium Chloride for Injection Concentrate and should not be used on any other drug product.
Information on container labels of large-volume injections can be a source of confusion and errors. To mitigate confusion involving large-volume injections, the container labels should be devoid of clutter, prominently state important information, and be adequately differentiated from other products.
Transferable or peel-off labels for injectable medications often do not provide the necessary information needed by the end user to verify the drug name(s) and strength before administration. Transferable or peel-off labels for injectable medications should contain sufficient information to identify the contents of the syringe. The transferable or peel-off label should not overlay or cover important information on the product label.
Pharmacy bulk packages (PBPs) should contain a predominately displayed statement reading “Pharmacy Bulk Package — Not for Direct Infusion” following the expression of strength.
The package type for injectable drugs for parenteral administration on container labels and carton labeling should delineate single-dose, multiple-dose, single-patient-use, PBP, or imaging bulk package. Container labels and carton labeling should differentiate a single-dose vial from a multiple-dose vial to alert the user to the appropriate use of the product.
To mitigate potential exposure errors with the use of insulin pens, a safety warning, “For Single Patient Use Only,” should be placed immediately below the product strength so that there is no intervening matter between the product strength and the warning. The FDA recommends using red‐shaded and bolded letters in a contrasting-colored box to enhance visibility and prominence.
Container labels for diluents should ensure that the word diluent is prominently displayed on the PDP to minimize the risk of the diluent being mistaken as the active drug.
Oral liquid drug products
Oral liquid drug product dispensing devices should be appropriate for the dosages to be measured using metric units and should not include any unnecessary markings on the dosing device that are not referred to in the product’s labeled dosage directions. For unit dose cups for oral liquid drug products, the strength should be presented as the total quantity per total volume to ensure that the quantity contained within the unit dose cup is clear to the end user.
Transdermal and topical systems
Transdermal and topical systems should include an identifying label on the backing membrane that includes, at a minimum, the drug name(s) and strength printed with ink that has adequate contrast with the background color and remains visible for the duration of system wear and after disposal to allow for proper identification of the product.
If unit dose packaging is intended for hospital use or institutional distribution and the container is not child-resistant, it is recommended that the sponsor include a statement on the carton labeling indicating the package is not child-resistant.
Infusion containers with hangers used for administration should ensure containers do not interfere with the ability to read the drug product information on the label, so sponsors should attach a transparent hanger to the container instead of using a portion of the drug label as the hanger. To increase the readability of the container label when the infusion container is hung upside down, the container label should prominently display the product’s proprietary, established, or proper name and the strength in an inverted manner on the bottom of the PDP or the side panel, and the sponsor should consider adding graduation marks in milliliters to the infusion container.
The FDA’s guidance highlights the importance of considering human factors when developing container labels and carton labeling. Marketed drugs and biological products can only truly be safe and effective if the container label and carton labeling are designed to promote safe dispensing, administration, and use of the product.
Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 or electronic comments to https://www.regulations.gov. Please reference docket number FDA-2013-D-0401 with all comments.
About The Author:
Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC and is an ASQ Fellow and SRE Fellow. Durivage primarily works with companies in the FDA-regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals) focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, has published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at firstname.lastname@example.org with any questions or comments.