Ryan A. Forrey, PharmD, MS

Spending on healthcare in the United States continues to be a major concern. In 2008 the United States spent $2.4 trillion on healthcare, which was 16.2% of the total US 

rose in 2009 to $2.47 trillion, or 17.3% of the GDP. If

this trend continues unabated, projections are that spending

will hit $4.4 trillion and top 20% of the GDP by 2018.

This continued rise in spending puts extreme pressure on

all facets of the healthcare industry. Patients, their families,

providers, payers, hospitals, and the government all

feel the stress. Clearly, this situation is not sustainable and

everyone must work to reduce healthcare costs.

In organized healthcare settings, one of the fastest-growing expense lines is prescription drugs. Drugs routinely consume 10% to 12% of total hospital expenditures, and in some specialty hospitals such as cancer hospitals, that amount is closer to 40% to 50%.

With an average cost of $800 million to bring a new drug to market, advances in treatment options come with a significant price tag.

 Many of the newer drugs are large-molecule monoclonal antibodies. These drugs typically are parenteral medications that come in single-use nonpreserved vials. Current United States Pharmacopeia (USP) Chapter 797 standards mandate that nonpreserved or single-use drugs must be discarded 1 hour after opening if that opening occurred outside of International Organization for Standardization (ISO) 5 air conditions, or after 6 hours if the vial was opened in ISO 5 air conditions and the drug remained in those conditions for the entire time.

 This USP standard was enacted to provide additional patient protection by minimizing the impact of any microbial contamination of these products that could result in patient harm. Even though these drugs are chemically stable, if unused amounts are present after the stated USP standard 

times, they must be discarded. This means that across

 the country significant amounts of high-cost drugs arebeing thrown away every year. In an audit of one of theoncology infusion clinics at Indiana University Health,the annual drug acquisition cost was approximately $15.5million and it was estimated that more than $1 million inviable drug product was discarded due to the USP 797standard.

If a mechanism could be established to ensure sterility of these drugs so that all of the product that was chemically stable could be utilized with little to no waste and no risk to the patient, then a significant amount of drug waste could be eliminated. As a result, the associated cost would be significantly lower.

In the last several years there has been growing interest in the use of closed system drug transfer devices (CSTDs) as a mechanism to protect healthcare workers from exposure to hazardous medications. The National Institute for Occupational Safety and Health (NIOSH), the American Society of Health-System Pharmacists, and the International Society of Oncology Pharmacy Practitioners (ISOPP) have all adopted a standard definition of a CSTD.

 According to these organizations, a CSTD is a device that “mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.”

 ISOPP summarized this definition as a system that is essentially leakproof and airtight.

Numerous studies have demonstrated the ability of the PhaSeal system by Carmel Pharma to meet this definition.

 However, to date the majority of these studies have focused on the ability of the PhaSeal system to prevent the escape of drug or drug vapor from the system.

Recently De Prijck and colleagues studied the ability of different systems, including PhaSeal, to prevent microbial contamination.

 In their study they inoculated the stoppers on vials with microbial contaminants and then utilized different mechanisms to enter the vials. They measured the amount of contamination present in the vials and concluded that the PhaSeal system did the best job of preventing transfer of contamination from the external vial stopper into the vial.

We wanted to build on the De Prijck et al study and consider the impact that a CSTD like PhaSeal could have on the ability to prevent contamination under normal working conditions. Clearly the De Prijck et al study created extreme conditions with the inoculation of the vial stoppers prior to entry. We believe that the PhaSeal system, properly applied in ISO 5 conditions, creates a mechanically closed system and the entry into PhaSeal via the double membrane also remains mechanically closed, essentially creating a scenario that mimics the sterility conditions present in an unopened vial. If this is indeed the case, then we should be able to use the chemical stability date to determine product expiration rather than the USP standard of 6 hours for products without a preservative that were accessed under ISO 5 conditions.

CLOSED SYSTEM TRANSFER DEVICE DESCRIPTION

The PhaSeal CSTD uses an in-built pressure equalization technique. The vial adapter, called a Protector, uses an expansion chamber that ensures that over-pressurization does not occur during drug preparation. The Protector attaches to the vial and penetrates the stopper with 2 cannulas. One cannula allows for the entry of the syringe needle, and the second allows for air to pass to the expansion chamber. An amount of air equal to the amount of medication must be added to the vial, and the excess air and hazardous medication vapors and particles travel through the cannula into the sealed expansion chamber. This effectively prevents aerosol and vapor leakage from the vial.

PhaSeal also uses a double membrane system to ensure leak-free transfer of drugs. A specially designed needle called an Injector is attached to a standard Luer lock connection syringe and used to access the vial via the Protector. The Injector contains an 18-gauge needle in a sealed chamber behind a membrane. The Protector has a similar membrane at the access point. When accessing

the vial, the Injector and Protector are assembled, and the 2 membranes are pressed against each other, creating a seal. The needle from the Injector passes through the dual membrane and into the vial. When removed from the vial, the needle passes back through both membranes, leaving the connection dry when disassembled. In this process, the hazardous drug does not come into contact with the atmosphere and all connections remain dry with no leakage occurring.

The NIOSH clarification also states that the intended function of a CSTD is to maintain sterility of the product.

 Therefore, a CSTD should not only protect the user from exposure to the hazardous medication, but also maintain the sterility of the product in the vial. If this is true, in theory a single-dose vial may be used with a CSTD for multiple uses without compromising sterility and integrity of the product.

We designed a multicenter study to simulate a variety of working conditions and equipment in different organizations. Testing was conducted at MD Anderson in Houston, Texas; Swedish-American in Rockford, Illinois; Indiana University Medical Center in Indianapolis, Indiana; and the James Cancer Hospital at the Ohio State University in Columbus, Ohio. All organizations followed current USP 797 standards in all facets of the study. Swedish-American utilized a compounding aseptic isolator to create their ISO 5 working conditions, whereas the other study sites used Class II Type 2 biological safety cabinets. Testing was conducted by trained intravenous pharmacy technicians during normal working hours and in normal working conditions. All microbiological testing and evaluation were conducted by an independent microbiologist.

The objective of the study was to assess PhaSeal’s ability to maintain product sterility over extended periods of time. The 

was that use of the PhaSeal System has no effect on product sterility and does not prevent microbial contamination and growth. The 

was that use of the PhaSeal System creates a system closed to microbial contamination and ensures product sterility. For this study, culture medium was utilized as the “product” being tested. The culture medium, which was prepared by an independent laboratory, was initially quarantined for 14 days and preincubated at the laboratory. All vials were observed for any overt evidence of contamination. Representative samples were also subjected to microbiologic examination to verify sterility.

All product manipulations in the pharmacy were performed in ISO 5 conditions utilizing either biological safety cabinets or compounding aseptic isolators as the primary engineering control. All primary engineering controls used in the study had evidence of certification to ensure operation within required standards as outlined in USP 797. All sites also utilized the same cleaning procedures during the study. Control culture medium was retained by the laboratory and kept in a controlled environment for continuous evaluation of any potential contamination. Control growth medium was also inoculated with a known quantity of 4 different known organisms and observed visually and microscopically at 24, 48, 72, 96, and 168 hours to verify the growth potential of the culture medium following preincubation. On day 7, the controls were sent to the pathology laboratory for analysis. Positive controls were also prepared by the pathology laboratory and tested for growth potential.

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The Phaseal closed system drug transfer device provides a mechanical barrier to the entry of contaminants into sterile solutions for up to 168 hours.