The pharmaceutical landscape is changing at a fast pace. Increases in manufacturing capacities all over the world and growing complexity of production processes have led to higher production speeds. Strict safety regulations and guidelines aim at optimizing and monitoring pharma production processes in order to reduce the risk of product recalls and protect consumers from contaminated medicine. Qualified inspection systems are among the most important quality safeguards for pharmaceuticals. The ability to evaluate processes in real time, to detect and quantify process- or component-related defects, and to take corrective actions is essential for process optimization and ultimately product quality and patient safety.

Patient safety and product quality must come first in pharma manufacturing processes. The development of biotech products and anti-cancer treatment, for example, is rising rapidly, requiring highly sophisticated technologies to inspect product at all levels. This is especially important for parenteral products filled in vials, ampoules, syringes and cartridges. Other liquid pharmaceuticals, as well as solid dosage forms such as tablets and capsules, also require thorough inspection. Technologies range from manual and semi-automated to fully-automated systems. They are used either for the detection of product-related contamination, cosmetic container defects, or both.

Product contamination occurs when particles or foreign matter are found within the drug product. Contaminated APIs (active pharmaceutical ingredients), foreign matter or filling material might get into the product during manufacturing or filling. Other means of contamination are particles from fractioned containers or human intervention. Cosmetic container defects, on the other hand, can already be present at the beginning of the process, or they might occur during handling, either by human intervention or by incorrectly adjusted machinery. Cracks in syringe flanges, or defects in the sealing integrity of ampules are some examples of container defects. Inspection methods applied depend largely on product consistency, and on form and size of the containers.

Human Intervention Still Indispensable
Manual inspection systems typically consist of a black-and-white background and fluorescent light. They require the operator to physically agitate each container to set the liquid and any contaminants into motion, and to carefully inspect each container. The human eye, however, is limited in its inspection possibilities, and depends on light intensity, distance, focus point, fatigue, performance variations, and many other factors, so manual inspection systems are mainly used for small batch sizes, produced for customized applications, laboratory analyses, and stability surveys. Other important fields of operation are evaluation of test sets, re-work of ejects, and benchmarking of fully automated machines, where they are practically indispensable. Semi-automated inspection systems reduce the need for manual handling; automatic feeding, sorting and discharging functions simplify the inspector’s manual work, enabling him to focus entirely on the quality control of containers. Thus, semi-automated machines achieve increased inspection accuracy and throughput rates.

Visual inspection systems require significantly less capital investment than fully automated ones. Covering a wider range of potential manufacturing flaws than automated equipment, they conform to regulatory standards. At the same time, they depend on human expertise and are subject to human errors that lie beyond the influence of the manufacturer. Yet manual and semi-automated inspection systems remain in wide use where the investment in automated machines would not pay off. The United States Pharmacopeial Convention (USP ) requires that particulate and other foreign matter visible to the human eye shall not be present. As a point of reference, a human inspector can detect approximately 50% of all particles sized 50 micron. Some automated inspection systems are able to detect particles below the human capabilities.

Automated Inspection Systems
Automated particle inspection systems have their origins in the 1970s. The “static division” (SD) technology derives its name from the ability to differentiate static from moving objects. It transmits light through the solution onto an optical SD sensor. Each container is inspected twice in real time. The container is rotated and then suddenly stopped. The liquid continues rotating in the immobile container. The insoluble foreign particles that now float inside the stationary container are depicted on the photo detector (SD head). Depending on the size and type of the particles, a portion of the transmitted light is blocked. These particles cast a shadow, which is detected by light-sensitive diodes. These changes in light intensity are only caused by moving particles, not by immobile objects, which significantly decreases the number of false rejects.

Since its introduction in 1975, SD technology has undergone various improvements and currently inspects the majority of parenteral products in clear solutions in over 50 countries worldwide. The new SDx sensor is equipped with many new software features. For instance, regressive testing software stores as many as 1,000 images for off-line tuning and viewing on mobile computing devices. Failed images can be saved in order to troubleshoot false rejects. To maintain the same number of inspection images for 300 and 600 ppm, SDx technology is equipped with a newly developed oscillating drive system. Like most fully automated inspection machines, those based on SD technology can be connected to filling and closing lines, other inspection machines, labelers, and cartoners. A smooth combination with other inspection methods is possible at any time.

Automated camera-based systems are used for both particle and cosmetic inspection. They also follow the principle of agitating the container and capturing images of light reflected from moving particles. As the containers are rotated by more than 360°, cameras take a series of high-resolution images. By comparing these images, the system identifies particles stuck to the sidewall, cracks in syringe flanges, as well as crimp or sealing defects. Pre-programmed parameters determine whether the container is rejected or accepted. Today, the capabilities of camera-based systems have greatly improved. Thanks to higher resolution and processing speeds, incorporation of artificial intelligence and neural networks, adoption of a graphical user interface (GUI), and high-quality CCD or CMOS cameras, these machines have developed into high-performance systems.

The Challenges and Opportunities of Process Analytical Technology
In 2004, the American Food and Drug Administration (FDA) issued its Process Analytical Technology (PAT ) guidance and caused considerable turmoil in the pharma industry. PAT is “a system for designing, analyzing, and controlling manufacturing through timely measurement (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.” The main focus of PAT is “building quality into products,” instead of inspecting quality after the product has already been manufactured. While some existing technologies (described above) inherently conform to these requirements, PAT guidance triggered the development of entirely new technologies for the in-line elimination of variable product quality, especially in the area of solid dosage forms.

Machines with X-ray technology offer comprehensive quality and weight control (for instance, of capsules). Software development and new imaging capabilities contribute to a rapid advance of these technologies. Most recently developed inspection units are able to simultaneously check all quality features like weight, foreign particles, deformation of capsule top and bottom, as well as length in real-time and at high throughput rates. Leak detection via high-voltage for the inspection of seal and container integrity also ranges among the technologies frequently used for glass containers (for example, ampoules).

Validating Inspection Processes
Compared to other pharmaceuticals, the production process of parenteral products is much more complex. It comprises mixing and filtering, followed by packaging into cleaned and pre-sterilized containers under sterile conditions. Parenterals are typically injected. They directly enter the bloodstream, and contamination and particulates might cause adverse reactions. The steps and components involved in the manufacturing process contain numerous risks of contaminants entering both process and product.
The EU Guideline to Good Manufacturing Practice, Annex 1 states, “[F]illed containers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. . . Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded.“   How this recording is done is up to each pharma producer.

Within the validation process, the creation and maintenance of samples is crucial to ensure that the inspection machine is maintaining the validated state under dynamic conditions. Furthermore, challenge set samples provide the basis for adjustment of inspection parameters. Manual and semi-automated inspection tools are well suited to inspect these samples. It is a common misconception that an automated machine is the only possibility to get the required inspection results, because the inspection process largely depends on the product, the type of defect, and the volume of the batch requiring inspection. On the other hand, even the best-trained human inspector cannot keep up with the high speeds of all production types.

Combinations on the Rise
The market for parenterals and especially generic products is experiencing enormous growth. Competition among manufacturers is increasing, leading to the use of more high-speed machines for high-volume production. Here, manual inspection is quickly stretched to its limits. How can pharma manufacturers best respond to growing control requirements? An example from another product quality-related issue might come in useful: drug counterfeiting is addressed by a multi-layer approach, including serialization, authentication and tamper-evidence. What proves successful in one area can be transferred to another: depending on the volume and the type of product and container, a combination of automated and manual inspection is sure to be most reliable. The number of manufacturers integrating different inspection technologies into their production processes both in-line and end-of-line will further increase in the near future.

To ensure that inspection machines operate at their best, manufacturers must pay attention to validation requirements and perform regular maintenance activities. They must also carefully monitor the process and check new regulations and guidelines, while also keeping apprised of the availability of new technologies. Depending on parameters such as volume, container type and size, as well as cost/benefit considerations, each manufacturer must determine the appropriate inspection method for his products. The possibilities of inspection technology are immense. So the decision for robust and reliable technologies is of utmost importance for high product quality. The keys to higher patient safety and minimized product recalls lies in knowing which inspection systems are available in the market — and in working with high-quality suppliers. 

References

1. Michael de la Montaigne, Pedro. J. Mendez, Ryosaku Tagaya: Inspection of Parenteral Products. Davis Healthcare International, 2009.
2. http://www.boschpackaging.com/eisaimachinery/

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Joachim Baczewski is president of Bosch Packaging Technology K.K. in Japan and Head of Inspection Technology. He can be reached at joachim.baczewski@bosch.com.