Chapter 51: In-Process and Finished Goods Inspections

The pharmaceutical industry has recognized the need for better and faster systems for inspection of in-process and finished goods. A wide range of inspection solutions exist, including visual inspection systems, vacuum decay technology, seal quality inspection, blister package inspection, and container leak testing. The implementation of one or more of these inspection methodologies allows drug manufacturers to eliminate catastrophic primary packaging failures and reduce the probability of product recalls while maintaining patient confidence.

In the case of sterile products, inspection methods such as vacuum decay testing, seal force, and dye penetration testing offer an alternative to the required sterility testing to ensure that the primary container maintains the integrity and quality of the drug product throughout its lifespan. According to the United States Food and Drug Administration (FDA) guidance “Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products,” some of the advantages of using these inspection methods are:

• A breach in container/closure system integrity can be detected before contamination enters the product.

• Results are timely. Sterility testing typically requires at least seven days of incubation to obtain results.

• The potential for false positive results can be reduced.

Inspection Methodologies

Most of the companies that provide this type of inspection technology offer nondestructive and noninvasive inspection methods that have the advantage of producing less waste. Some of the current technologies in the marketplace include seal quality inspection, nondestructive leak testing, and blister package inspection.

Seal Quality Inspection (Airborne Ultrasound)

This method is commonly used to inspect the seal quality of medical pouches and other types of flexible packages by transmitting an ultrasonic signal along the seal. The signal creates a high-resolution image of the seal structure and quality. By using this method, container defects such as abrasion, blisters, contamination, incomplete and/or misaligned seal, delamination, wrinkles, flex cracks, crooked seal, and cut seal can be identified.

Nondestructive Leak Testing (Vacuum Decay)

This technology uses the principle of changes in vacuum to determine if leaks are present in the container, thus giving an indication of the quality and integrity of the primary package container. This inspection methodology is used to inspect filling components such as presterilized stoppers and presterilized caps, and drug product packaged in vials, syringes, and ampules. One of the advantages of this method is that the test is nondestructive and noninvasive; therefore, no sample preparation is required.

Blister Package Inspection and Container Leak Testing

Blister package inspection (vacuum decay with indirect imaging) is a nondestructive and noninvasive method used for inspection of drugs packaged in blister packages. Leak detection is accomplished by detecting the change in pressure inside the test chamber resulting from gas or vapor egress from a blister package challenged with vacuum. If leaks are present, the inspection diagnostics are capable of identifying the defective blister cavities. The container leak testing (pressure decay) method uses changes in pressure to detect the presence of leaks in the container.

Freeze-Dried Product Leak Testing

Freeze-dried (lyophilized) products were previously inspected for vacuum using a spark test, but new methods are being implemented. The leak testing is performed by analyzing the headspace pressure inside the vial using laser absorption spectroscopy (optical measurement of any gas that is present). This method is nondestructive and gives an indication of the actual vacuum level in the vial. Typically, the equipment used for this type of testing has an automatic self-test system that challenges the machine by using calibrated check vials, thus ensuring the reliability of the equipment.

Vision Inspection Systems

These types of systems help the drug manufacturer analyze the quality of the product, identify product or container defects, and ensure that the data printed on the primary and secondary containers are accurate (for example, drug facts, labels). Most visual inspection system companies agree that the key factors in a visual inspection technology are lighting and optics. Lighting in relation to the geometry of the container being inspected should be considered when choosing a visual inspection system, and optics can help when trying to increase contrast between the region of interest (container or drug being inspected) and the background. For example, drug companies use visual inspection systems to inspect blister packages to make sure that they contain the correct color tablets.

Qualification and Calibration

Drug manufacturers must ensure that the inspection technology used is qualified and that any inspection processes used in their operations are validated. The inspection technology selected must be appropriate for the product that will be inspected, and the qualification needs to prove that the equipment is reliable when identifying the characterized product/container defects.

This type of equipment should be routinely calibrated, inspected, and checked according to a written program designed to ensure proper performance. Written procedures for cleaning, operating, and maintaining the automated equipment should be in place. All such programs and procedures must be approved and followed.