Defining the Sterile Barrier of Complex Drug Delivery Systems

New injection-delivery systems, such as auto-injectors, recombinant syringes, and retractable needles, have introduced new challenges to package validation and product development, particularly for container closures. These delivery systems may have multiple closure points and more complex manufacturing processes with increased opportunities to introduce manufacturing related defects. For complex delivery systems, the final system is an orchestra of the individual components working together. Each component coming in contact with the critical product path must be validated to provide a reliable sterile barrier. With additional fitment contact points comes greater risk that one of the fitments will contribute to a container-closure integrity (CCI) failure. Taking a clear approach to developing the methods used to validate and assure CCI early in the process is crucial in providing a solid platform for product launch. 

Defining a sterile barrier
CCI is defined as the ability of a package to prevent ingress of microorganisms, chemicals, and environmental contaminants and to retain the contents of the package, thus ensuring the product meets physiochemical and microbiological specifications. CCIT is focused on detection of leaks in the sterile barrier of a package. A maximum allowable leakage limit must also be defined, because most package types demonstrate at least miniscule gaseous leakage, in addition to permeation, even when optimally designed and assembled.  

CCIT is a growing regulatory concern for all packages, and new, complex delivery systems introduce unique challenges. Before a CCIT method can be established, the sterile barrier for each package format must be defined.  Although a package may have several seals, a single barrier should be identified as the sterile barrier.  For a glass vial, this barrier includes the rubber stopper and glass body of the vial. The crimp contributes to the barrier but is not a portion of the sterile barrier field.

Certain component fitments may have multiple closure points as the sterile barrier, such as the ribs on the plunger of a prefilled syringe. One closure point is in contact with the product.  The outer closure point is in contact with the non-sterile environment.  The space between the ribs represents a unique no-man’s land of sterility.  If one is breached, what does this mean in terms of CCI?  Is the barrier breached? A syringe tip presents similar controversy, with a complex sterile barrier mechanism that includes the needle shield and syringe-tip cap. One contact point protects the sterility of the product, and the second contact point provides a sterile barrier to the delivery contact point (e.g., needle or nozzle).  Integrity of the overall system can be determined to assure there is no leakage of the closure system. Between the closure points, however, there is often space that must remain sterile and free from contamination by outside contaminants and from the product itself.  Interclosure sterile space must be challenged for sterility, and few tests exist to challenge the integrity of this space on a final assembled component.  When designing a delivery system, designing multiple sterile barrier closure points seems logical in an effort to reduce the risk of a breach of the sterile barrier. The multiple closure points, however, can present challenges that are both difficult to test and manage. Ultimately, for each package format, a clearly designed and defined sterile barrier is an important step in establishing CCI. 

This article was excerpted from an article that will be published in the April issue of Pharmaceutical Technology.

Oliver Stauffer is vice president and COO and Heinz Wolf is general manager at , info@ptiusa.com.