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
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
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