Twenty five years ago, the concept of using an isolator in pharmaceutical and hospital applications was only a far out thought. The original “BUGS” (Barrier Users Group) was in its formative stages as an idea to improve sterility assurance of aseptically filled parenteral products. Containment of hazardous drugs was accomplished by putting the operator in a “space suit.”
By the early 1990s the pharmaceutical industry, working with the FDA, were evaluating the isolator concept as a means of not only increasing sterility assurance but reducing facility cost. Companies were testing isolation systems by running over a million vials without a single unit being contaminated. The isolators supported by effective decontamination technology through the use of vapor phase hydrogen peroxide allowed for larger batches and extended run times. The 2004 FDA guidance document “Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice” delivered to manufacturers a message that the agency not only recognized the technology, but encouraged it as a means of producing products with a higher sterility assurance level.
Societies embraced the education of both users and regulators by conducting seminars, workshops, and Web casts. ISPE (International Society of Pharmaceutical Engineering) held the 20th Annual Barrier Conference in June 2011. Jack Lysfjord has chaired the conference since the initial meeting in 1991. Jack has been the historian for the aseptic use of isolators publishing each year the number and type of aseptic filling lines using the technology.
The other focus of isolators in pharmaceutical and biotechnology is their use for containment of the highly potent drugs. Isolators as a barrier around the product, rather than individuals wearing PPE (personal protective equipment) while handling potent drugs, have become almost a necessity as the drug exposure levels of new compounds has become lower and lower. Targeted therapy of the new classes of drugs has caused the amount of drug causing an adverse effect to drop into the nanogram range. Such small quantities are beyond the safe handling capabilities of conventional downflow booths or Class II biological safety cabinets.
What does the future hold? The future lies in the support technologies in terms of the ability to measure both from an aseptic and containment application of the technology. As measurement improves, incremental improvements in terms of how individuals interact with the process within the isolator will occur. Robotics and on-line feedback systems will be two areas of advancement.
On the pharmacy front, laminator flow workbenches for preparing IVs and biological safety cabinets were the main line of engineering controls used to protect compounded preparations twenty five years ago.
Pharmacy isolators were introduced in England in the early 1990s. The first isolators in the United States began appearing in the mid to late 1990s. The use of isolators for compounding was driven by regulations created by state pharmacy boards until 2004. In 2004 USP (United States Pharmacopeia) produced a standard (General Chapter <797>) requiring pharmacies compounding sterile preparation to provide facilities to improve the sterility assurance level of these preparations. Patient deaths in several states were the driver behind the need for a national standard. Although the standard, which was reissued in 2008, is technically enforceable by FDA, the enforcement is state by state through pharmacy boards. Some states have actually refused to adopt the standard.
USP <797> has adopted the terms CAI (compounding aseptic isolator) and CACI (containment aseptic compounding isolator) to differentiate between isolators used for compounding non-hazardous and hazardous preparations. The primary difference between the two is pressurization with the non-hazardous being positive pressure and the hazardous being negative pressure. Pressurization has been a means of secondary containment. Studies (“Exposure to Antineoplastic Drugs in Two UK Hospital Pharmacy Units”) have shown no difference in exposure levels between hazardous drugs prepared in positive and negative isolators. The same study did show that the use of isolators significantly reduces exposures compared to Class II biological safety cabinets used to compound antineoplastic drugs.
Currently USP <797> allows for either ISO Class 7 cleanroom or the use of an isolator not located in a cleanroom. Hazardous drugs can be compounded in either a Class II biological safety cabinet or an isolator.
What does the future hold? The future focus will be on improving sterility assurance levels to improve patient safety. Unlike aseptic pharmaceutical applications, the decontamination of materials being placed into the isolator is manual and therefore not consistent or repeatable. Companies in both Europe and the United States have introduced isolators with vapor phase hydrogen peroxide capabilities to reduce surface micro contamination in the last few years. This is a critical step in reducing secondary infections. The next major advancement yet to be introduced is the use of robotics to facilitate the transfer of drugs from vials to the final patient delivery package