A discussion of the past should be more than an exercise in historical review. It should provide a look at where we were as context for measuring how we have evolved and as pretext for predicting where we are going. Such is the case when looking back over 30 years at the development of packaging and delivery systems for injectable drug products. Although the components have changed very little in appearance, the material science and manufacturing technologies that go into their creation have undergone significant advancement.
The drive for quality and cleanliness
The most notable change to pharmaceutical packaging and packaging components during the past 30 years has been the rapidly increasing emphasis on closure cleanliness. Pharmaceutical manufacturers must ensure the purity of their drugs and provide products that are safe for patients and for those administering the drug. To this end, manufacturers specify packaging systems and components that eliminate, as much as possible, the risks to quality that stem from particulates, processing aides, extractables, and leachables.This emphasis on cleanliness has been driven primarily by the increased number of biopharmaceuticals. This is not to imply that the industry was not quality-focused 30 years ago. On the contrary, the industry has a strong reputation for product purity. During these three decades, however, standards for packaging systems and components have evolved to meet the requirements for containing and delivering increasingly sophisticated drug products.
As pharmaceutical product development and manufacturing have improved since 1977, so, too, have delivery systems and components. Today, component manufacturing in classified areas and cleanrooms (up to Class 100 [ISO 5]) is commonplace. Thirty years ago, manufacturing proceeded in environments that were far from clean in the pharmaceutical sense. Component manufacturers now operate in environments conforming to current good manufacturing practice (CGMP) regulations, whereas 30 years ago, adherence to CGMPs was not required. As another example, ultrahigh quality now can be achieved with sophisticated electronic vision inspection, whereas 30 years ago, quality was highly dependent on the vision of plant employees.
The difference in component manufacturing between now and 30 years ago is astounding to those who are not familiar with the processes. Although the manufacturing processes then and now appear nearly identical, the technologies and systems behind the processes are radically different. For example, today's elastomer manufacturing facility is extremely high-tech. From the receipt of raw materials to the shipping of final products, every step is documented and measured to ensure traceability. These procedures are in place to ensure a high-quality product is delivered. Quality encompasses everything from traceability throughout the manufacturing process through the collection of in-process data and the improved cleanliness of the final product.
A visitor to a plant in 1977 would find an operation that bore scant resemblance to a pharmaceutical manufacturing facility. Thirty years ago, primary packaging components—that is, components such as stoppers and syringe plungers in contact with the packaged drug—were manufactured from elastomeric materials, many of which contained dry natural rubber. The manufacturing process consisted of blending the raw materials to form a sheet of rubber. The individual parts were formed by compression molding. A molded sheet could have hundreds or even thousands of individual parts that were trimmed in a die press. Some trimmed parts were washed, and others were packed in plastic bags for shipping to the customer. The components were frequently treated with silicone oil as a means of overcoming the tackiness inherent in an elastomeric product. Without some form of lubrication, the components would not process in a pharmaceutical filling line. Silicone oil, however, can transfer from the closure to the drug product.
To reduce reliance on silicone oil, component manufacturers developed films and coatings that provided lubricity for filling-line performance and provided a barrier against extractables. In the 1970s, a fluorinated ethylene-propylene (FEP) coating was applied to the drug contact side of serum stoppers, providing both a barrier and lubricity. The film adheres readily to the flat surface of a serum stopper or syringe plunger, but it cannot be applied to the more complex geometric shapes of lyophilization stoppers. To solve this problem, component manufacturers used films made from other fluorocarbon materials. These materials are conformable and provide excellent barrier protection. Further, fluoro-elastomer films have superior lubricity properties.
Another option for enhancing component performance on filling lines is a crosslinkable siloxane-based coating that is cured on the surface of elastomer components by ultraviolet light. This type of coating provides lubricity but does not have barrier properties.