Injectable Administration Systems

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.

Stoppers and syringe plungers are not the only primary packaging components undergoing change. Many new drugs, especially those used for oncology, are sensitive to the glass used to manufacture vials and syringe barrels. Contaminants from the glass might leach into the drug product which in some instances can be worth thousands of dollars per dose. This new generation of high-value biopharmaceutical therapies requires equally high-value packaging and administration systems to maintain the drug's biological integrity and to maximize its therapeutic benefits.

Some manufacturers are switching their products from glass vials and syringe barrels to products manufactured from cyclic olefin copolymers (COC) and cyclic olefin polymer (COP) materials. These resins are inert and have properties such as extremely low extractables, high heat resistance, excellent low-temperature characteristics, excellent drainability, and low-moisture permeability that are favorable for high-potency, high-value drugs.

A deliberate evolutionary process

The transformation to today's primary pharmaceutical packaging environment, with an emphasis on quality and cleanliness, proceeded deliberately with the focus on creating a CGMP environment. From the manufacturing floor and into a company's day-to-day operating procedures, CGMP regulations represented a huge shift in thinking. They required improved traceability of the raw-materials chain; the introduction of new systems for quality control and quality assurance testing of raw materials, work in progress, and finished goods; and a tightening of manufacturing and operating procedures and product specifications to achieve new levels of quality.

Today's plant has the cleanliness one would expect in pharmaceutical manufacturing. Employees in manufacturing and processing areas wear protective clothing appropriate for the work space's classified environment to keep particulate and fibers out of the manufacturing area, and they are trained thoroughly in CGMP requirements. The quest for quality begins even before raw materials are received at the plant. Materials are purchased on the basis of a supplier's ability to meet tight tolerances and strict quality standards.

Moreover, incoming raw materials are sampled and tested; the lots are not released for production until the laboratory determines that specifications have been met. Today's elastomeric formulations are blended from fewer materials that are less extractable. The formulations used 30 years ago would not be acceptable for new drug products today because of concerns over extractables and leachables and because some of the materials used in the 1970s would not meet current industry guidelines. In addition, the properties of today's elastomers, including coring and resealing properties, help pharmaceutical manufacturers meet shelf-life requirements and provide better performance during administration. Further, today's elastomers have helped improve the manufacturing process. As a result, molding yields fewer rejected parts.

Today, mixing equipment used to blend the ingredients that go into elastomeric formulations is closed to minimize contamination. The calendaring and extrusion processes can achieve tight dimensional tolerances for the sheeting that is used to mold the components. Improved equipment and quality systems such as in-process metal detectors help ensure the highest quality finished components.

Molded sheets of components move from molding to trimming, where a die trims the individual parts from the sheet. Today's trim dies operate at a high level of precision. The result is components with very little dimensional deviation from the standard and fewer instances of particulate from the trimming process.

Postmanufacturing processes also have advanced significantly. In today's manufacturing environment, downstream processing frequently includes washing in a pharmaceutical-grade washer to yield ready-to-sterilize components that are shipped to manufacturers. Final rinse processes use water-for-injection and final packing is conducted in a Class 100 cleanroom. The bags used to pack the washed components are suitable for direct entry into a sterilizer.

The contrast with 1970s processing is striking. Three decades ago, most components were trimmed and dropped into a poly bag. The bag was secured with a twist tie and shipped to the customer in a corrugated box. Component washing was rudimentary compared with today's process; the wash did little more than remove lubricants applied during the trimming operation.

The impact of regulatory guidances

Guidances issued by the US Food and Drug Administration have had a strong influence on the drive to cleanliness and ultrahigh quality.

In 1999, FDA released Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. The container-closure guidance created a fundamental shift in the relationship between pharmaceutical manufacturers and their suppliers. The Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing, released in September 2004, was intended to help pharmaceutical companies meet CGMP regulations when manufacturing sterile drug and biologic products in aseptic processing environments. These guidances defined FDA's thinking about issues related to primary packaging and administration-system components and added to the pressure on pharmaceutical manufacturers to manage their filling-line risks. As regulatory requirements for packaging components have changed, pharmaceutical manufacturers have become more vulnerable to FDA inspections and, if violations are found, to actions that could affect their manufacturing operation.

The development of barrier isolation technology, although initiated nearly 20 years ago, finally began to take hold in the early 1990s. Isolator technology requires packaging components clean enough to be introduced directly into an isolator unit.

Starting in the 1990s, pharmaceutical manufacturers had the option to mitigate some of the component preparation risks by buying components that were ready to use (RU) or ready to sterilize (RS). This option, in addition to helping mitigate risk, also helped to streamline their operations by eliminating the component preparation steps. Nonetheless, the effect on the component manufacturer was dynamic. Processing RS and RU products required cleanroom facilities for washing and final packing, the addition of sterilization equipment, and the development of expertise in and knowledge of microbiological testing. Those carefully prepared components are now shipped in plastic boxes loaded on plastic pallets. It is necessary to eliminate corrugated boxes and wood pallets because they are a potential source of particulates and contamination. Today, RU components are just entering the market. Thirty years ago, a product with these characteristics would have been hard to imagine.

A changing pharmaceutical industry

Changes in the pharmaceutical industry research and manufacturing technologies have driven significant developments in packaging and delivery systems.

The increase in the number of large-molecule, biopharmaceutical drugs in development pipelines has added to need for injectable packaging and administration systems. The old glass-and-elastomer closure systems may not provide the effective barrier properties needed for high value, life saving therapies. Component manufacturers have responded with new materials and technologies that ensure extended drug-product shelf life.

Many new biotechnology-derived drug therapies are unstable in liquid form and therefore are introduced as lyophilized or dry-powder dosage forms. Lyophilized drugs need special stoppers for optimal performance in lyophilization chambers. The stoppers must solve the problem of the stopper sticking to the lyophilization shelf after the cycle is completed. In addition, lyophilized drugs typically are reconstituted at the point of care, thus requiring patient friendly administration systems.

The increase in self-administered therapeutics

Thirty years ago, healthcare revolved around hospital care. Today, because of cost constraints and the introduction of maintenance-type drugs for treating chronic conditions such as arthritis, cancer, multiple sclerosis, and other diseases that require frequent medication, healthcare revolves around the home. Many of the maintenance therapies are delivered by injection, spurring a need for patient-friendly administration systems. These systems must ensure the potency of the drug, be tamper evident, help deter counterfeiting, promote compliance with a dosing regimen, ensure dosing accuracy, and be as safe, easy to use, and painless as possible.

An outgrowth of these changes is the move from the typical vial and disposable syringe to a prefillable syringe. With prefillables, dosing accuracy is ensured. Prefillables, however, present some challenges for the industry. A pharmaceutical company needs a prefillable system that will protect the integrity of the packaged drug product over time and will function as represented over the full shelf life of the drug product. The response from component manufactures was the development of syringe plungers with barrier films that minimize the interaction between the packaged drug and the components. At the same time, the industry has developed elastomers for molded plungers that maintain functional properties such as seal integrity and breakloose and extrusion forces.

When self-administered drugs are in lyophilized or dry-powder form, manufacturers must find methods or packaging systems that help prevent accidental needle stick injuries, incomplete mixing, inaccurate dosing, and drug spray-back. Manufacturers familiar with the drug administration process must provide delivery systems that simplify drug reconstitution, especially for nonprofessional caregivers.

What's next?

Packaging and delivery systems as a differentiator for drug products will continue to become more important, especially in crowded therapeutic areas and for solving industrywide problems such as drug-product counterfeiting. The market today is receptive to packaging systems that can provide track-and-trace capabilities and product authentication throughout the supply chain. Pharmaceutical seals are an ideal platform for these technologies. We can expect to see wider use of technologies such as radio-frequency identification (RFID) tags embedded in the plastic button affixed to the seal or ultraviolet inks applied to the seal. RFID has the potential to provide item-level security that can help secure the supply chain.

The drive for cleanliness and purity will no doubt continue into the foreseeable future. With advances in material science, we can expect cleaner elastomeric formulations for manufacturing primary packaging and delivery-system components. We also can expect coatings with near-total barrier properties. Processing aides such as silicone oil will be eliminated and quality levels will approach a zero-defects standard.

As the great Yogi Berra said, "It's tough to make predictions, especially about the future." But we, as package component and drug administration system manufacturers, can make one prediction with confidence: As pharmaceutical research continues to develop advanced, life-saving therapies, the systems used to package and administer those therapies will keep pace through advances in material science and innovative design.

Fran DeGrazio is the vice-president of marketing and strategic business development at West Pharmaceutical Services, 101 Gordon Dr., Lionville, PA 19341, tel. 610.594.3190, fax 610.594.3325, fran.degrazio@westpharma.com

Where were you 30 years ago?

Fran DeGrazio entered the industry in 1983 by working for six months at Pierce and Stevens Chemical Corp. before joining West Pharmaceutical Services. She has been with West ever since, serving various functions in the analytical laboratory, research and development, and customer technical support areas as well as being vice-president of quality assurance (Americas) and director of the regulatory group. In 2006, she assumed her current role.