Packaging Operations and Controls

One of the most important functions that the product packaging provides is the protection of its contents. The identity, strength, and purity of the drug product can become compromised if the packaging component that is in direct contact with the dosage form contaminates the product and/or fails to protect it from environmental conditions such as temperature, humidity, and moisture.

In addition to the evaluation and qualification of the primary packaging components (those that come in direct contact with the product), drug manufacturers need to evaluate the suitability of the secondary packaging components, as a failure in packaging performance may translate to potential quality problems. For example, secondary packaging components such as cartons that are intended for additional light-exposure protection need to be controlled to ensure that the cartons are not removed while the product is in storage.

The regulations for manufacturing of container closure systems detail the qualification and controls around the primary packaging components, as well as the variables to consider when selecting a primary packaging component (for example, vial, syringe, ampule, stopper) for the dosage form. This chapter, however, only addresses the aspects of operations and controls related to the secondary packaging components (for example, cartons, pallets) and how the secondary packaging plays a role in the protection of the product.


According to the United States Food and Drug Administration (FDA) guidance for industry, “Container Closure Systems for Packaging Human Drugs and Biologics,” the secondary packaging components are used for several purposes:

To provide protection from excessive transmission of moisture or solvents into or out of the packaging system

To provide light protection for the packaging system

To provide additional microbiological protection by protecting the packaging system from microbial intrusion

To provide protection from excessive transmission of reactive gases (atmospheric oxygen, inert headspace filler gas, or other organic vapors) into or out of the packaging system

The secondary packaging offers a means for product identification and presentation. For


example, cartons and packaging inserts commonly are used to display information related to drug facts, dosage, and expiration dates, and as such, the information presented on them is governed by good manufacturing practices (GMP). On this subject, the Federal Food, Drug, and Cosmetic Act (FD&C) states that a drug or device shall be deemed to be misbranded if packaging and labeling are inappropriate, unrecognizable, misleading, or allow inks or adhesives in contact with the product. A particular type of packaging that grants additional security to the final drug product is the tamper-evident package, which can be designed as the primary packaging, secondary packaging, or a combination of both packaging systems. Currently, the Agency requires this type of package for most over-the-counter (OTC) drug products. The definition as stated in 21 CFR 211.132 is “A tamper-evident package is one having one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of successful tampering and to increase the likelihood that consumers will discover if a product has been tampered with, the package is required to be distinctive by design or by the use of one or more indicators or barriers to entry that employ an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture).”

In summary, drug manufacturers are facing numerous challenges when it comes to ensuring the compliance and security of the final package while maintaining brand recognition and shelf presence (especially for OTC drugs). As a result, manufacturers need to balance cost efficiency, regulations, and the new trends around child-resistant and senior-friendly packaging.


To ensure adequate control of the packaging and labeling operation, drug manufacturers must exercise at minimum several GMP:

Packaging line identification, indicating the type of product and lot number being packaged.

Inspection of production facilities before the packaging/labeling operation to ensure that packaging and labeling materials from other lots are not present. An additional inspection of the facilities should be conducted at the end of the packaging operation.

Examination of packaging and labeling materials before use to determine their suitability for the packaging operation.

Proper maintenance and calibration of the packaging and labeling equipment.

Label control, including packaging insert controls.

Clear and detailed standard operating procedures and batch production records that allow for documentation of the key steps of the packaging operation (lot number, line-clearance procedures, label reconciliation, number of units packed, and results of the work-in-progress [WIP] inspection and packaged product inspection).

Segregation of packaged product that needs to undergo inspection by the quality unit.

Prevention of cross-contamination or errors by physical separation of different packaging/labeling operations.

Controls over contract manufacturers that perform the secondary packaging and labeling operations.

Control of labels. Most manufacturers are changing from cut labels to roll labels; however, where cut labels are used, drug manufacturers need to control the packaging operation by dedicating packaging lines using automated or semiautomated equipment for inspection of packaged product, and ensuring 100 percent visual inspection of the finished product for hand-applied labeling. Generally, the visual inspection is verified by a second individual who did not perform the initial 100 percent inspection.

Additionally, the personnel involved in the packaging and labeling operation must have the required training and experience to perform their assigned duties. Personnel qualifications must be current in order to support the different inspection activities performed throughout the packaging and labeling operations. Equipment changeovers and setup are critical when the production lines are used for packaging and labeling of different products. FDA has issued Form 483 observations for drug manufacturers failing to maintain control of the packaging line as a result of deficiencies in personnel training. An FDA 483 observation regarding this subject cited the manufacturer for failure to adequately train employees engaged in the manufacture, processing, or holding of a drug product in GMP or in the particular operations performed by the employees [21 CFR 211.25(a)]. For example, employees engaged in the production of 260 mg/26 mL liquid oral product, lot #XYZ, which was mislabeled as 20 mg/2 mL, did not follow the company’s written procedures pertaining to product changeover on the Auto Labe labeling system or those requiring documentation of filler settings.


Figure 53.1 depicts the steps in a typical final packaging process. Common operations in the packaging of pharmaceuticals include:

Inspection of packaging and labeling materials to determine suitability for use.

Inspection and verification of the packaging line (equipment) to ensure that the equipment is ready for use.

Other preparation activities, which include verification of batch records being present in order to document the packaging/labeling operations.

Label application to primary packaging (labeling equipment). 

Packaging inserts application (cartoner).

Product in its primary packaging is placed in cartons (cartoner), that is, single dose per cartoner or multiple doses per cartoner.

Product is collated and arranged on pallets for storage or distribution.