• Industry's requirements for ultra-clean, ultra-high quality packaging and administration systems and system components
• Regulatory guidances driving industry's need for risk mitigation
• Advanced technologies for pharmaceutical manufacturing
• A shift in health-care delivery to the increasing use of self-administered drugs
Quality and cleanliness
The most notable change to pharmaceutical packaging materials has been the increasing emphasis on closure cleanliness. Pharmaceutical manufacturers must ensure the purity of their drugs and provide products that are safe for both the patients and for those administering the drug. To achieve these standards, manufacturers are specifying packaging systems and components that eliminate, as much as possible, the risk to their drugs caused by particulate, processing aides, extractables, and leachables.
This emphasis on cleanliness has been driven by the emergence of biopharmaceuticals and is taking hold in the industry in general. That's not to say that the industry was not quality-focused years ago. On the contrary, the industry turns on its reputation for product purity. Over the years, however, standards for packaging systems and components have evolved to meet the requirements for containing and delivering increasingly sophisticated drug products.
The emergence of biotechnology-engineered therapeutics has created a considerable shift in the pharmaceutical industry. Chemically derived drugs are no longer the driving force in new drug development. The focus has shifted to biologics and with that so too does the packaging and delivery mechanisms that need to be in place to protect the integrity of the drug. Throughout the last several decades, manufacturers have developed sophisticated packaging and delivery systems to support the requirements of traditional and more complex biologic drugs. Increased focus on quality and cleanliness ranks high in importance.
Just as pharmaceutical product development and manufacturing have come a long way, so, too, have delivery systems and components. Today, component manufacturing in classified areas and clean rooms (up to Class 100 [ISO 5]) is commonplace; more than a quarter century ago, manufacturing proceeded in environments that, in the pharmaceutical sense, were far from clean.
Today, component manufacturers operate in a cGMP environment; back then, adherence to cGMPs was not required.
Today, ultra-high quality is achieved with systems such as sophisticated electronic vision inspection; in 1970, quality was highly dependent on the vision of plant employees.
The difference in component manufacturing then and now is astounding to those who are not familiar with the processes. Although the manufacturing processes from the two eras appear nearly identical, the technologies and systems behind the processes are radically different.
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 assure 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 1970 would find an operation that bore scant resemblance to a pharmaceutical manufacturing facility of today. Thirty years ago, primary packaging components--such as stoppers and syringe plungers that contact 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, while 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 itself.
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 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 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 for vials and syringe barrels. Contaminants from the glass can leach into the drug product which in some instances can be worth thousands of dollars per dose. This new generation of high-value, life-saving 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 from glass vials and syringe barrels to 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, drainability and low moisture permeability that are favorable for high-potency, high-value drugs.
Deliberate evolutionary process
The high standard of quality and cleanliness within the pharmaceutical packaging environment came as a deliberate decision to create a cGMP environment. From the manufacturing floor and into a company's day-to-day operating procedures, cGMPs represented a huge shift in thinking. CGMP's came into play in the 1990s for component manufacturers. It required improved traceability of the raw materials chain; introducing new systems for quality control and quality assurance testing of raw materials, work-in-progress and finished goods; and tightening manufacturing and operating procedures and product specifications to achieve new levels of quality.
Today's packaging plant resembles a pharmaceutical manufacturing facility; the level of quality and cleanliness are set to the same high standards for both. 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. They are trained thoroughly on cGMP requirements.
The quest for quality begins even before raw materials are received at the plant. Materials are purchased based on the suppliers' ability to meet tight tolerances and strict quality standards.
Incoming raw materials are sampled and tested; the lots are not released for production until the lab determines that specifications are met. Today's elastomeric formulations are blended from fewer materials that are less extractable. The formulations used many years ago would not be acceptable for new drug products today because of extractable and leachables concerns and because some of the materials used in the 1970s would not meet today's industry guidelines. In addition, the properties of today's elastomers help pharmaceutical manufacturers meet shelf-life requirements and provide better performance during administration, such as coring and resealing properties. Further, today's elastomers have helped to improve the manufacturing process. As a result, molding yields fewer rejected parts.
The mixing equipment used to blend the ingredients that go into the elastomeric formulations is closed to keep outside contaminants to a minimum. The calendaring and extrusion processes are able to achieve the tightest of dimensional tolerances for the sheeting that will be used to mold the components. Improved equipment and quality systems, such as in-process metal detectors, help ensure the highest quality finished components.
The molded sheet of components moves 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 a component with little dimensional deviation from the standard and fewer instances of particulate from the trimming process.
Post-manufacturing processes have also advanced significantly. In today's manufacturing environment, downstream processing frequently includes washing in a pharmaceutical-grade washer to yield components that are shipped to manufacturers ready-to-sterilize. The final rinse uses water-for-injection and final packing is done in a Class 100 clean room. The bags used to pack the washed components are suitable for direct entry into a sterilizer.
The contrast to 1970s processing is striking. Three decades ago, most components were trimmed and dropped into a plastic 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.
Impact of regulatory guidances
Guidances issued by the United States Food and Drug Administration (FDA) have had a strong impact on the drive to cleanliness and ultra-high quality. In 1999, the 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, September 2004, was intended to help pharmaceutical companies meet cGMP regulations when manufacturing sterile drug and biologic products using aseptic processes.
These guidances defined the FDA's thinking on 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 have an impact on their manufacturing operation.
The development of barrier isolation technology, while 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 the 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 to mitigate risk, also helped to streamline their operations by eliminating the component preparation steps. However, the impact on the component manufacturer was dynamic.
Processing RS and RU products required clean room facilities for washing and final packing, the addition of sterilization equipment and the development of expertise and knowledge of microbiological testing.
Those carefully prepared components are now shipping in plastic boxes loaded on plastic pallets. It is necessary to eliminate corrugated boxes and wood pallets because of their potential source of particulate and contamination.
Now, ready-to-use components are just entering the market--a product with these characteristics would have been unimaginable three decades ago.
The changing pharmaceutical industry
Changes in 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 increased the 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 assure extended drug product shelf life.
Many of the new biotechnology-derived drug therapies are unstable in liquid form, and as a result, are introduced as lyophilized or dry powder dosage forms. Lyophilized drugs need special stoppers for optimal performance in lyophilization chambers. The stoppers must solve a problem of the stopper sticking to the lyophilization shelf (where the vials sit during the process) after the cycle is completed. In addition, lyophilized drugs typically are reconstituted at the point-of-care (home health care), thus requiring "patient-friendly" administration systems.
Packaging and delivery systems as a differentiator for drug products will continue to become more important, especially in crowded therapeutic areas and for solving industry-wide 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 can also 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. [HCP]
--By Frances L. DeGrazio, Vice President, Marketing & Strategic Business Development, West http://www.westpharma.com/NA/EN/ABOUT/Pages/default.aspx. DeGrazio is a member of the Parenteral Drug Association (PDA), American Chemical Society (ACS) and the American Association of Pharmaceutical Scientists (AAPS). Fran holds a B.S. degree in Chemistry from Cabrini College in Radnor, PA.