Diabetes is the first non-infectious disease that has taken on the magnitude of a pandemic. In parallel, research has made great progress in recent years and pharmaceutical companies are making insulin available across the globe. However, it also requires particular care during all process steps. Particles in the product and container defects are not acceptable. Hence, insulin producers not only require sophisticated filling technology but also advanced inspection systems to protect both product and patients.

According to the International Diabetes Federation, 12% of global health expenditure—approximately $727 billion—is already spent on diabetes treatment. This is not surprising, considering that 425 million adults suffer from diabetes worldwide, and over one million children and adolescents currently live with type 1 diabetes.¹ These figures are increasing every day. Nevertheless, there is also good news: the once deadly disease has turned into a chronic one. Thanks to new, targeted therapies and application technologies for insulin administration, people who are suffering from diabetes today have the same life expectancy chance as their peers.

Biosimilars, solutions and suspensions
Human insulin is obtained from bacteria using biotech methods. Since 1996, modified insulins have also been approved. Referred to as insulin analogs, they work particularly quickly or uniformly. During the past years, insulin analog patent expirations have triggered the market entry of biosimilars in many countries, leading to different manufacturing processes and stricter inspection requirements. Insulin is delivered either as a solution or as a suspension. While a solution is a homogeneous mixture in which one substance is dissolved in another and cannot be separated, a suspension is a mixture of liquids with solid particles which may not dissolve in the liquid. The latter is a challenge for visual inspection.

In the treatment of diabetes, pen systems that can be equipped with insulin cartridges and injection needles have long surpassed all other injection systems, mainly due to their ease of use and relatively inexpensive production. The insulin pens are loaded with cartridges—a glass cylinder which is closed on the top end by an aluminum cap with a puncture membrane and at the bottom end with a rubber stopper. While easy and safe handling is the most important criterion for patients, insulin manufacturers must pay particular attention to sterile filling and to the integrity of both the product and the packaging materials used.

Product safety and quality come first
Manufacturers, physicians, and patients alike are scrutinizing product quality more closely than ever, and production processes are subjected to the review of regulatory agencies. The pharmaceutical industry is looking to reduce manual intervention during the production process as much as possible. Modern barrier technology completely seals off products, processes, equipment, and operators from each other. Restricted Access Barrier Systems (RABS) ensure effective separation in the sterile room. Insulin manufacturers increasingly rely on the use of isolators, which are an optimum solution for both product and operator protection. Compared to conventional cleanrooms, they ensure a higher Sterility Assurance Level (SAL) at lower operating costs. Moreover, robotic solutions are used to a great extent to handle the cartridges during the filling process.

The process a cartridge runs through includes many steps: washing, siliconizing, sterilizing, filling and closing in the isolator device, then inspection, and tray loading. The cartridge is exposed to different temperatures, pressures, and movements during these processes. Filling and closing machines with a capacity of up to 600 units per minute² are considered state-of-the-art and are installed in the market in large numbers. The higher the speed, however, the more the containers, stoppers and caps are subject to physical stress. This is where inspection technology comes into play: it is a key quality safeguard for pharmaceuticals and contributes significantly to patient safety.

From cracks to particles
Cosmetic container defects can, for instance, be detected using sophisticated camera technology. But cracks, chips or fractures that lead to breakage on the way to the patient or during usage are not the only risk for insulin cartridges. The product itself can also be contaminated. Product contamination implies the undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter into or onto a raw material, intermediate, or API during production, sampling, packaging, storage or transport.³

Intrinsic contamination can occur during the many steps of the filling and closing process and include packaging material particles, or process-generated matter such as metal or glass. Extrinsic particulate matter, on the other hand, has its origin in the production environment and can consist of dust, fibers or biotic containments, or even human hair or skin. Inherent particles, finally, are those originated from the formulated product itself.⁴

In general, particles are classified as subvisible up to a size of 100 micron. They pose greater risks to patients from a clinical perspective, since they are present in all solutions to a certain extent and cannot always be fully identified. From 100 micron onwards, we talk about visible particles. As a point of reference, most automated inspection machines can detect particles down to a size of 50 micron.

SD technology for particle inspection
Automated particle inspection systems have their origins in the 1970s. One of the original automated inspection principles is the static division (SD) system, which was developed by Eisai Machinery, now part of Bosch Packaging Technology. The SD system derives its name from the ability to differentiate static from moving objects. It transmits light through the solution, which is then focused onto a linear array of optical sensors. Before inspection, the container is rotated to put the liquid contents and any present particles in motion, and then suddenly stopped. After the container is immobilized, the liquid and any present particles continue moving by inertia during a definite time, during which signals from the SD sensor array are read out.

The moving foreign particles momentarily block a portion of the transmitted light casting a shadow over the sensors, which is detected as a time-dependent differential signal. These differential changes in light intensity can only be caused by moving particles, in contrast to any other possible static shadow arising from smears or defects in the container. In such a way, only particles are detected by a very simple method without interference from physical features on the container. Since its introduction in 1975, the SD technology has undergone various improvements and currently inspects most parenteral products in clear solutions in over 50 countries worldwide.

Camera-based particle inspection
For particle inspection, SD technology is still the preferred choice by many. Nevertheless, there are several use-cases where camera systems can be an alternative or an add-on feature to support automated vision systems delivering high quality particle inspection results. Hence, choosing the suitable camera hardware can be a key decision in designing an inspection system. Line scan cameras, for instance, are especially suitable to detect particles in suspensions. These cameras are typically used, amongst others, to inspect insulin cartridges for particles that stick to fixed areas such as the stopper or the glass surface. Moreover, line scan cameras help to identify and verify the mixing balls in cartridges, which are needed to achieve a better homogenization of the suspension.

Camera-based cosmetic inspection
Cameras are also used to identify cosmetic container defects—more specifically automated camera systems using the latest CCD (charge coupled device) and CMOS (complementary metal oxide semiconductor) sensor technologies in combination with specially designed optics and LED lighting. These systems can be highly complex, since they need to cover the entire container and inspect it from many different angles. Hence the most important question when developing such inspection technology is which defects are truly critical.

For insulin applications, several distinct positions of the cartridge need to be carefully examined. The cartridge neck is especially prone to cracks, which are not easy to detect. Some insulin products are filled with a small air gap at the top of the cartridge. The main challenge consists in the distinction between measuring the filling level and detecting potential cracks. Both the upper and lower body of the cartridge must be inspected for cracks in separate sections. Bottom cracks from the side and from below are especially critical because this section presents the plunger side interface to the injection pen later during the manufacturing process. These cracks can lead to cartridge breakage during pen application.

Some inspection machines for insulin cartridges are equipped with more than 30 different camera stations. This allows pharmaceutical manufacturers to differentiate between different error categories classify them into minor and major defects. This enables them to draw important conclusions about the production, filling and packaging process—and to continuously improve the quality of these processes.

Market growth requires integrated platforms
Cost pressure is omnipresent in the highly competitive insulin market. Consequently, manufacturers can only generate profit through higher production volumes. In addition to the cost factor, the growing number of diabetes patients in the emerging economies has driven major insulin manufacturers to expand their production to more and more locations worldwide. Machines for the processing of cartridges for insulin pens are increasingly used particularly in the so-called “pharmerging” markets, such as India, Russia or China. The criteria for insulin lines are output, high availability, reproducible precision and the highest safety in insulin production.

To meet the industry’s rapidly changing requirements, new high-end machines offer a hybrid approach by integrating both SD and camera-based inspection technology in one flexible platform. This enables pharmaceutical manufacturers to adapt their inspection items and processes to their individual needs. Moreover, a modular machine design facilitates the expansion of existing systems by additional inspection units or an extra inspection module. These machines aim at high detection rates and are particularly suited for suspensions such as insulin.

References

1. http://www.idf.org/diabetesatlas
2. https://www.boschpackaging.com/en/pa/products/industries/pd/product-detail/mld-4933.php
3. https://www.pharma-iq.com/glossary/contamination
4. “Visual Inspection and Particulate Control”, D. Scott Aldrich, Roy T. Cherris and John G. Shabushnig, PDA and DHI Publishing LLC, 2016.