The number of people suffering from diabetes is increasing rapidly worldwide. In parallel, the global market for insulin therapies is growing at a much faster rate than total sales of prescription drugs. For diabetics who depend on insulin, pen systems that can be equipped with insulin cartridges and injection needles have long since become the preferred injection systems. To help ensure the safe filling of insulin cartridges, manufacturers offer new technologies that ensure high output, low product loss, and optimal patient protection.  This article will look briefly at some of the manufacturing issues and the technology being used to fill pens and other leading insulin delivery systems.

Diabetes mellitus is the first non-infectious disease that has taken on the magnitude of a pandemic. A once deadly disease has become chronic. Thanks to new, targeted therapies and application technologies for insulin administration, people who are suffering from diabetes today have the same life expectancy as their peers. The current figures are frightening, however: 382 million people worldwide suffer from diabetes. It is estimated that the number will increase to 592 million by 2035.  Most people with diabetes—about 80 percent—live in countries with medium to low income, with an increasing percentage in the emerging economies.

Forms of Diabetes
In type 1 diabetes, the body’s own immune cells are directed against the insulin-producing beta cells of the islets of Langerhans in the pancreas. This often happens in childhood. What triggers this misguided immune response has not yet been fully explained, but insulin treatment is always needed for type 1. Type 2 diabetes, in contrast, results mainly from lifestyle choices.  Obesity and lack of exercise lead to a resistance to the insulin hormone, preventing it from working properly on the cell membranes and from transporting glucose into the cells. The result is increased blood glucose concentration, which can go unrecognized for many years.

All approaches to diabetes therapy have always aimed at controlling blood sugar levels and preventing large fluctuations down (hypoglycemia) or up (hyperglycemia). In the 1920s, researchers Frederick Banting and Charles Best were able to extract insulin and successfully treat a young patient with it for the first time.  A disease that had been fatal up to that point suddenly became manageable. Today, insulin is obtained from bacteria using biotech methods and brought to the market as human insulin. Since 1996, modified insulins or insulin analogs have also been approved.

Changing Diabetes Therapies and Delivery Methods
Technical innovations since the 1980s have made domestic self-monitoring of blood glucose possible—an important advance for the calculation of the insulin dose, giving patients a bit more flexibility. Insulin pens were developed for more ease of delivery. The pens are used as multiple application systems with pre-filled insulin cartridges.  For diabetes patients the independent administration of insulin is now a lot easier. Due to their shape, the pens cannot only be transported more conveniently, they can also be applied “en route” without attracting attention. Patients are able to better adapt the therapy to their own rhythm of life. Another milestone was the development of insulin pumps, which continuously and flexibly provide diabetes type 1 patients with short-acting insulin.

While needle-free injection systems do not yet have great penetration in the market, several developments promise further improvements in the quality of life of diabetes patients. One such example is inhalable insulin. Although the first commercial trials from around 2006 initially failed, a comeback may be imminent: The U.S. Food and Drug Administration (FDA) is presently reviewing the inhalation formulation of an American pharmaceutical manufacturer.  Further studies are currently underway, including ones on the development of orally administered insulin. 

Safety of the Product and Patient
Due to the worldwide increase in the number of people suffering from diabetes and constant improvements in therapy and delivery methods, the global market for insulin is growing continuously, along with the market for pens and other injection aids. Currently pens are the most widely used system for insulin injection, mainly due to their ease of use and relatively inexpensive production. The insulin pens are loaded with cartridges. The cartridge is a glass cylinder which is closed on the front end by an aluminum cap with a puncture membrane. The rear end of the cartridge is closed with a rubber stopper. For diabetes patients, easy and safe handling of the pens is the most important criterion. Insulin manufacturers in turn must pay particular attention to sterile filling and to the integrity of the materials used.

Product safety is the highest priority for pharmaceutical manufacturers. For this reason, the pharmaceutical industry looks 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) (Photo) ensure effective separation in the sterile room. Insulin manufacturers also increasingly rely on the use of isolators, which ensure higher product quality at lower cost compared to conventional cleanrooms.

Market Growth Requires High Output
Cost pressure is omnipresent in the highly competitive insulin market. As it is not possible to establish a high price for insulin preparations, manufacturers can generate profits only through volume. Although insulin pumps are even easier to use compared to pens, their higher production costs made it impossible for them to prevail globally. 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. That is why machines for the processing of cartridges for insulin pens are increasingly used particularly in the “pharmerging” markets such as India, Brazil, and China. The criteria by which manufacturers choose their machines are high output, high availability, and reproducible precision in insulin production.

Filling and closing machines for cartridges with a capacity of up to 600 units per minute are now considered state-of-the-art, and are already installed in the market in large numbers. Filling lines integrated in isolator systems run continuously for 21 days in some cases, thus ensuring maximum productivity. In terms of filling systems and processing of the packaging, the industry demands ever greater flexibility. That is why modern plants and lines are compatible with all current filling technologies and partly also equipped with combi filling stations for several packaging types, such as cartridges, vials, and injection bottles or syringes.

Focusing on Glass Integrity
Each insulin cartridge must go through many steps: washing, siliconizing, sterilizing, filling and closing in the isolator device, inspection, and tray loading. The cartridge is exposed to different temperatures, pressures, and movements during these processes, all of which it must withstand unscathed. The higher the speed of a filling and closing machine, the more the manufacturing process subjects the glass to physical stress. This can cause damage to the glass, such as cracks, chips, or fractures. The product loss caused by these defects results in higher costs for pharmaceutical producers, which machine manufacturers are counteracting with new solutions for gentle processing.

The primary objective of these innovations is to minimize contact between glass containers. During loading of the cleaning machine, for instance, the cartridges are loaded onto the conveyor belt in just one row and then transported in rows. Stainless steel containers, referred to as “transport pucks,” ensure smooth transportation from the washing station through the sterilizing tunnel by preventing glass-to-glass contact. This is particularly important for the processing of dual-chamber cartridges, as they may be even more fragile due to the internal bypass.

Adjusting the Physical Stress
During the sterilization process, the glass is exposed to an enormous heat influence. The high temperature leads to expansion of the glass mass in the tunnel. This can be compensated for by a conveyor belt with flexible lateral support, which widens immediately after the tunnel entrance. To keep the cartridges from tipping over, they are transported to the inlet of the filling machine in bulk, where a star wheel separates them again. The angle of the star wheel must be designed precisely, facilitating seamless loading of the receiving pockets in the star wheel with cartridges. Robotic feeding and removal of cartridges can provide further reduction in physical stress.

Cosmetic glass defects are evidence of damaged packaging, which may also break on the way to the patient or be contaminated with particles after the filling and closing process. Exact and correct closure of the cartridges is essential for safe drug administration, where 100% inspection plays an important role. With the “Static Division” (SD) technology, light is projected through the liquid onto an optical sensor, which allows differentiation between moving particles and static objects. Automatic camera-based systems in turn detect both particles and cosmetic defects. While the containers are rotated by more than 360 degrees, cameras take high-resolution images. By comparing these images, the system is also able to identify particles adhering to the walls or defects in the cap crimping.

Precise Filling for Safe Dosing
The filling of insulin products into a cartridge must meet special requirements. On the one hand, insulin suspensions often require filling with a homogeneous level of active ingredients. On the other hand, full and bubble-free filling should be ensured without overfilling. This demands a two-step filling process, in which 80% of the maximum quantity is dosed into the cartridge in the first step. In a second station, the remainder is filled to the full point by laser-scanning the cartridge neck. The laser sensor switches off the dosing when the fluid meniscus reaches the laser beam. Suspensions require constant homogenization of the product template and often also require that mixing bodies (sterile glass balls) are added to the cartridge. This enables the patient to perform simple homogenization of the suspension by shaking prior to application. The glass ball feeding is also monitored using sensors.

Research for a Better Quality of Life
Even at an early developmental stage of insulin preparations, safe filling of cartridges is top priority for the subjects in clinical trials. Insulin producers therefore have a great need for manual and semi-automated test machines for product development. New, highly flexible laboratory modules are primarily used in early clinical phases. It is particularly important that these machines can be equipped with different filling technologies and allow the filling parameters to be easily transferred to production systems via scale-up at a later point. Inspection is equally important during product development: manual inspection systems, supported by cameras where required, quickly and accurately inspect empty and full glass containers for particles in the liquid or for cosmetic defects.

It is still uncertain when alternatives to injecting insulin will prevail. For the time being, insulin pens are set to maintain their status as the preferred application system. But the near future already promises the introduction of further insulin formulations and new, improved insulin pens. The artificial production of the insulin hormone—from the first extraction in the twenties until the introduction of the first long-acting insulin analog in 2000—is a success story unparalleled in medicine. Although prevention and avoidance of long-term consequences must always be top priority, advances in treatment provide people affected by diabetes with the hope of further, significant improvement in their quality of life.

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Johannes Rauschnabel, PhD, is Chief Pharma Expert at Bosch Packaging Technology. He is a graduated Chemist from Eberhard-Karls-University Tuebingen and has more than 25 years of experience in research and development and 15 years in the pharmaceutical industry as a product manager for Barrier Systems and as Director Process Engineering. Johannes Rauschnabel is a frequent speaker at conferences, a lecturer at University of Hohenheim and an author of multiple scientific papers and patents.

References

1. http://www.idf.org/diabetesatlas
2. Merkel, Howard: How a Boy Became the First to Beat Back Diabetes, http://www.pbs.org/newshour/rundown/how-a-dying-boy-became-the-first-to-beat-diabetes/, January 2013.
3. Freissmuth, Jérôme: Developments of Drug Delivery Devices are Increasingly Focused on Patients’ Needs, www.chemanager-online.com/en, April 2013.
4. White, Ronald D.: MannKind is seeking approval for diabetes inhaler system by spring, http://articles.latimes.com/2013/dec/08/business/la-fi-stock-spotlight-mannkind-20131209, December 2013.
5. Yaturu, Subshashini: Insulin therapies: current and future trends at dawn, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596776/, February 2013.