James A. Jorgenson, RPh, MS

	In the wake of the New England Compounding Center tragedy, calls for greater controls over compounding pharmacies has spurred legislative activity in both the US Senate and the House of Representatives. State boards of pharmacy and the US Food and Drug Administration (FDA) have also increased regulatory scrutiny of these operations, resulting in the closure of additional compounding pharmacies in multiple states.

Growing concern over the continued supply of quality products have many hospital pharmacies either evaluating “insourcing” sterile compounding operations or already actively engaged in these processes. By controlling the supply, production, and quality themselves, hospital pharmacists feel more assured of safer and consistent patient care surrounding the use of these compounded sterile preparations. Legislative Activity: Deciding Which Agency Has Oversight Nationally, the Senate’s Health, Education, Labor, and Pensions Committee (HELP) recommended that the FDA should be granted greater authority to regulate compounding pharmacies. The HELP Committee subsequently approved the Pharmaceutical Compounding Quality and Accountability Act (PCQAA).

	Under this proposed legislation 3 categories for sterile compounding would be created. The fi rst category would cover traditional compounding by pharmacies, wherein products are prepared pursuant to individual patient prescriptions. This category would include hospitals and hospital systems where anticipatory compounding occurs for products in advance of a prescription for use solely within the hospital system. This type of traditional pharmacy compounding would continue to be regulated by state boards of pharmacy. The second category clearly establishes that drug manufacturers would “continue tobe regulated by the FDA.” The third category presents a new approach to regulate large-scale drug compounders. The PCQAA terms these operations to be “compounding manufacturers” and defi nes them as businesses that produce “sterile compounded drugs in advance of a prescription and sells them across state lines.” Under the proposed Senate legislation, the door would be open for pharmacies to expand inhouse sterile compounding operations consistent with the requirements of the individual state boards of pharmacy.

	Not surprisingly, the House of Representatives has adopted a different approach to this issue. The House Energy and Commerce Committee does not support giving the FDA more authority in this area, stating that it already has full authority to act to improve oversight and quality of compounded sterile products. To date, the House subcommittee seems more focused on continuing to analyze what went wrong with the New England Compounding situation and why the FDA did not respond more aggressively to previous quality and compliance issues that were documented for this compounding center.

 In view of this approach to the problem, hospital pharmacies would still be open to moving forward with expanding their internal sterile compounding operations.

	Detail of the procedures and requirements for compounding sterile preparations are delineated in the United States Pharmacopeia (USP) in Chapter <797> Pharmaceutical Compounding: Sterile Preparations. It also establishes standards that are applicable to all practice settings in which sterile preparations are compounded. USP <797> seeks to protect patients from harmful large content errors and microbial contamination of compounded sterile products.

 All of the USP chapters that fall below 1000 can be enforced by the FDA, adopted by state boards of pharmacy, and surveyed against by The Joint Commission. In fact, a 2011 survey found only 17 states directly referenced USP <797> in part or in its entirety as part of their individual state practice requirements.7 Many states are in various stages of retooling their regulations and how they will reference USP <797> as concern continues to escalate sterile compounding. It is also important to  recognize that USP <797> is not a static document. The USP Sterile Products Expert Committee is continuously monitoring research and practice to suggest improvements to chapter <797> and revised chapters are periodically issued by the USP.

	Pharmacies considering insourcing sterile products should be ready to adopt USP <797> as their minimum practice standard. This includes compliance with its recommended facility requirements, training, documentation, process control, and quality requirements.

	One of the key elements for consideration by pharmacies is the risk level of the products that they will be compounding. USP <797> has established standards for low-, medium-, and high-risk compounding.

		Simple admixtures compounded using closed system transfer methods

		Prepared in International Organization for Standardization (ISO) Class 5 Primary Engineering Control (PEC)

		ISO 5 PEC is located within an ISO 7 Buffer Room with an ISO 8 ante area

		In the absence of a sterility test, the maximum beyond-use dates (BUDs) are 48 hours room temperature, 14 days refrigerated, and 45 days frozen

		Prepared in ISO Class 5 primary engineering control (PEC)

		Compounding area is segregated from noncompounding areas but is not an ISO 7 Clean Room

		Administration must start no later than 12 hours after preparation

		Admixtures compounded using multiple additives and/or small volumes

		Complex manipulations (eg, total parental nutrition)

		Located in ISO Class 7 buffer area with ISO Class 8 ante area

		In the absence of a sterility test, the maximum BUDs are 30 hours room temperature, 9 days refrigerated, and 45 days frozen

		Located in ISO Class 7 buffer area with separate ISO Class 8 ante area

		Examples include products prepared from bulk, non-sterile components, or fi nal containers that are non-sterile and must be terminally sterilized

		In the absence of a sterility test, the maximum BUDs are 24 hours room temperature, 3 days refrigerated, and 45 days frozen

	The majority of products considered for insourcing by hospital pharmacies will fall in the medium-risk category. But high-risk compounding should be considered as well, given the ongoing national drug shortages. Many critical products may only be prepared by using non-sterile ingredients and terminally sterilizing the final preparation, which constitutes high-risk compounding. Additionally, any pharmacy considering insourcing sterile compounding should also be aware of Drug Enforcement Agency (DEA) requirements if controlled substances such as patient-controlled analgesia syringes are being considered as part of the compounding formulary.

	With USP <797> as the minimum standard for a hospital-based sterile compounding program, hospital programs should also consider working toward an enhanced level of quality using Good Manufacturing Practice (GMP). GMP is a production and testing procedure that helps to ensure a quality product with no harm to patients.8 GMP compliance is mandatory for commercial pharmaceutical manufacturing. The majority of hospital pharmacies in Europe follow GMP for their sterile compounding. Hospital pharmacies considering insourcing sterile compounding should also explore GMP to safeguard their patients and reduce risk associated with this process to the maximum extent possible and to avoid any future need for majorr reengineering.

	GMP guidelines are not prescriptive instructions on how to manufacture products, but rather are the principles that must be observed when hospitals build their quality programs and manufacturing processes. There will be many ways GMP requirements can be met. Each hospital will need to determine the most effective and efficient processes a GMP program would include. These should incorporate, but not be limited to, the following areas:

		Clearly defined manufacturing processes with specified validation to ensure consistency and compliance with hospital formula specifi cations.

		A change control process for any manufacturing changes to ensure that there is no negative impact on the quality of the drug and that all modifications are properly validated.

		Complete documentation for all procedures written in clear and concise language.

		Training and certifi cation programs for all personnel working in this operation.

		Creation of an appropriate record-keeping system to demonstrate that all the steps required by the defined procedures are in fact taken and that the quantity and quality of the drug is as expected.

		A process to investigate, document, and act on any deviations to the standard protocol.

		Creation of a record-keeping system for manufacture and product distribution that enables the hospital to trace the complete history of any batch created.

		Development of a distribution process that meets state board of pharmacy and DEA requirements to minimize any risk to the quality of the drug products prepared.

		A workable system for accurate recalling of any batch of drug prepared.

	While quality, safety, and supply are the primary issues driving hospitals to consider insourcing sterile compounding operations, economics can also play a part in the decision making. Larger healthcare institutions that outsource signifi cant amounts of compounding and repackaging may experience costs that exceed a million dollars annually. With impending cuts to government reimbursement under healthcare reform, hospitals and health systems are looking for any and all opportunities to reduce their expenses. Even though insourcing sterile compounding generally requires an initial investment in capital and personnel, if done correctly these programs can provide a positive return on investment. In the past, a major cost was the construction of a USP-compliant ante room and clean room confi guration. A traditional “fixed wall” clean room setup could easily require amillion dollar investment for a larger operation. Currently, modular clean room options provide a quick and easy option that offers a “self-contained” solution that can be dropped into a warehouse type of space with minimal HVAC work. These modular options can also be expanded, reconfigured, and moved as requirements dictate, presenting a more versatile and cost-effective option for hospitals considering insourcing.

	With increasing regulatory oversight for sterile compounding and a limited ability to assure the quality of compounded sterile products obtained from external compounding pharmacies, many hospital pharmacies are moving to insource these products. In making this decision, hospitals are gaining greater control of the quality, safety, and supply of these products. Done correctly, hospitals can also improve patient care options and institutional financial performance.

	However, organizations embarking on this path should have a clearly defi ned plan to ensure compliance with all applicable regulations and standards to operate the safest possible program. Organizations moving in this direction must determine their internal level of expertise and consider outside assistance, if necessary. The most efficient physical and operational options must be clearly delineated to ensure that the best return on investment is realized.

Articles

With increasing regulatory oversight for sterile compounding and a limited ability to assure the quality of compounded sterile products obtained from external sources, many hospital pharmacies are moving to insource these products.

Improving Compounding Safety: New Regulations and Options for Institutional Insourcing

Use of closed-system transfer devices (CSTDs) has become an integral part of the processes associated with preparation of hazardous medications. Traditionally, CSTDs have been used to reduce the amount of exposure to hazardous medications experienced by healthcare workers. However, 1 device in particular, PhaSeal (Carmel Pharma AB, Goteborg, Sweden), has also been proved to prevent contamination and potentially extend the beyond use date (BUD) of pharmaceuticals otherwise limited by US Pharmacopeia Chapter 797 (USP <797>) sterility limits, which has the potential to decrease waste.

 Decreasing waste would not only provide significant cost savings for healthcare systems, but also assist with preventing wastage of medications that are in critical short supply.

Healthcare costs in the United States continue to be an area of great concern. Projections indicate that sometime between 2018 and 2020, the healthcare budget in the United States will increase to more than 20% of the gross domestic product. Traditionally, the rate of growth of drug expenditures has exceeded the rate of growth of total healthcare expenditures.

 In recent years, there has been equilibration between the rate of growth of total healthcare costs and the rate of growth of pharmaceutical costs. The Centers for Medicare & Medicaid Services has projected a 5.2% growth rate in overall healthcare expenditures in 2011. However, clinic-administered antineoplastic agents have seen much higher increases in cost growth. For example, there was a 9.5% increase in costs between 2009 and 2010. As such, there is tremendous potential in this area for significant cost savings.

At the same time that US healthcare costs are a concern, there is also an increased focus on improving quality and safety. To ensure patient safety associated with the use of parenteral medications, USP <797> contains standards for healthcare facilities to use as guidelines when preparing compounded sterile products. Furthermore, USP <797> is enforceable by the Food and Drug Administration (FDA) and can be surveyed by The Joint Commission or adopted by state boards of pharmacy. In particular, current USP <797> standards mandate that nonpreserved or single-dose vials must be discarded 1 hour after punctured if the puncture occurred outside of International Organization for Standardization (ISO) 5 air conditions, or after 6 hours if the vial was punctured and retained in an ISO 5 environment.

 However, it should also be noted that USP does allow for extending the BUD based on studies conducted to demonstrate the validity of the extension. While these standards are aimed at improving patient safety and ensure sterile product integrity, they also increase waste and overall healthcare cost due to the relatively short BUDs imposed.

The currently accepted definition of a CSTD endorsed by the National Institute for Occupational Safety and Health, the American Society of Health-System Pharmacists, and the International Society of Oncology Pharmacy Practitioners is “A mechanically closed system that prevents the entry of contaminants into the system or the escape of drug or drug vapor out of the system.”

 Numerous peer-reviewed published studies have demonstrated the ability of the PhaSeal system to meet this definition.

 Additionally, the FDA has recently taken a position on CSTD technology by announcing its intention to establish a new product code, labeling standard, and testing definition for CSTDs. The new standard will provide clarity in the future, as there has been much debate among manufacturers about the validity of products claiming to be a CSTD.

To date, the majority of studies utilizing the PhaSeal system have focused on its ability to protect healthcare workers. In other words, studies have focused on the second part of the CSTD definition—prevention of “the escape of drug or drug vapor out of the system.” However, our group recently conducted and published a study that examined the first component of the CSTD definition: the prevention of “the entry of contaminants into the system.…” The rationale for our first study was to demonstrate how the use of the PhaSeal system would maintain a closed-system environment that would allow for an expansion of the BUD. By preventing the entry of contaminants into the system and maintaining a sterile environment, PhaSeal could extend the use of these products and help reduce the amount of viable product being discarded. Using a multivariate interrupted time analysis, our results demonstrated a 98.2% probability that the vial contents would be sterile at 168 hours. One limitation of the study was the method of “opening up” the CSTD to perform subcultures. Although this was necessary to identify any contamination, it does not apply to compounded sterile product control issues from a real-life perspective.

Accordingly, we designed a second study to improve on our methodology and eliminate this variable. Intravenous (IV) bags were utilized, and 100% of each of the primary test vial contents was distributed into 5 IV bags of sterile culture medium via the PhaSeal CSTD under study. This procedure eliminated the major variable from our first study that may have contributed to observed contamination. As in our first study, we conducted this study at 4 different centers: the University of Texas, MD Anderson Cancer Center in Houston, Texas; the Swedish American Hospital in Rockford, Illinois; Indiana University Health University Hospital in Indianapolis, Indiana; and The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital in Columbus, Ohio. Three centers used a biological safety cabinet (BSC) and 1 used a compounding aseptic containment isolator as their primary engineering control. For secondary engineering controls, 3 sites had USP-compliant negative-pressure ISO 7 clean rooms, and 1 site had a USP-compliant isolator room (negative pressure with at least 12 air exchanges per hour). All primary and secondary engineering controls were certified to be operating within USP standards. All samples were collected during normal working hours under normal working conditions.

The objectives of this second study were the same as those of the first study.

 The primary objective was to assess the ability of the PhaSeal system to maintain product sterility given current USP <797> and ISO guidelines for use. The second objective was to determine whether the vials could be used over an extended period of time while maintaining sterility.

Our primary testable hypothesis for this study was identical to that of our previous work. The null hypothesis was that utilization of the PhaSeal System has no effect on product sterility and does not prevent microbial contamination and growth. The alternative hypothesis was simply that the PhaSeal system does have an effect on product sterility and will prevent microbial contamination and growth.

For this study, culture medium was utilized as the “product” being tested. The culture medium was prepared and handled as in the first study by an independent laboratory. Pretesting and posttesting quality assurance was conducted on both the vials and IV bags of culture medium. Quality assurance testing included the use of positive and negative controls. The culture medium was initially quarantined for 14 days and pre-incubated at the laboratory, and 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 a biological safety cabinet or a compounding aseptic containment isolator 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.

The following equipment and supplies were used for this study:

• Culture medium vials (Bio-Med QC tryptic soy broth 20 mL, The American Society of Microbiology, USP).

• Culture medium bags (Bio-Med QC tryptic soy broth 100 mL, The American Society of Microbiology, USP).

• Sterile/nonsterile gloves, sanitized periodically.

• Sterile isopropyl alcohol pads (medium).

• Sterile isopropyl alcohol 70% spray bottle.

. Ten each of the PhaSeal Protector, Adapter, and Injector assemblies were placed in the primary engineering control (PEC). Hands were washed and gloves were donned and sanitized prior to work in the PEC. The ISO class 5 work surface and the materials that were introduced into the hood were sanitized with 70% isopropyl alcohol according to USP <797> standards. Consecutively numbered “day 0” bag labels were affixed to the front of selected 100-mL tryptic soy broth (TSB) bags. Matching numbered vial labels were affixed to selected vials. Initially, 10 complete test setups were placed in the PEC. Following the first batch setup, test IV bags, vials, and disposables were placed in the PEC by an assistant to preclude the operator from having to remove his/her hands from the PEC. The operation became somewhat continuous, with the assistant providing a flow of new test materials and removing used bags and vials for storage and shipping to the lab. The operator resanitized his/her gloved hands periodically throughout the sample run. The glove resanitization goal was to perform that operation before each of the 10 sample preparations. The first 100-mL TSB IV bag was hung from the IV bar. The cap was removed from the matching numbered 20-mL TSB vial. The vial septum was sanitized by wiping with alcohol across the top, from the septum across the aluminum rim, in a unidirectional motion 1 time. The alcohol was allowed to dry for at least 10 seconds. The PhaSeal Protector was removed from its wrapper aseptically by only touching the expansion bell or the green cap. The injection port remained sterile. The cap of the PhaSeal Protector was aseptically removed from the bottom side and placed over the injection port of the PhaSeal Protector. The PhaSeal Protector was attached to the vial. The spike port cap of the IV bag was removed, and the port rim was sanitized with an alcohol swab. An Infusion Adapter was aseptically removed from its sterile packaging and inserted into the 100-mL IV bag of TSB. The injector was attached to a 5-mL syringe and then 4 mL of air was drawn up. The cap of the Protector was removed and the syringe-Injector combination was engaged. After air was injected into the vial, the vial was inverted and 4 mL of TSB was withdrawn. The syringe-Injector combination was detached from the vial-Protector combination. The syringe-Injector combination was attached to the port on the Infusion Adapter, which had been attached to the IV bag. A second Protector was opened, and the sterile cap was attached to the TSB vial to protect its injection port during storage outside of the PEC. The new Protector was discarded. The contents of the syringe were injected into the IV bag. The Injector/syringe assembly was disconnected from the Infusion adapter/IV bag assembly and discarded. Intravenous bag 1 and the Protector-vial combination were placed in a plastic zipper bag to protect them if they were stored outside of an ISO-5 environment. The procedure was repeated for the remaining day 0 preparations (83 total). The entire procedure from day 0 was repeated at days 1 (24 hours), 2 (48 hours), 3 (72 hours), and 7 (168 hours).

Experimental Design Overview and Microbiologic Testing.

 The study test medium used was TSB in 100-mL IV bags and 20-mL vials as used in the Bio-Med QC, LLC, media-fill aseptic technique test kits. Each participating institution received 83 vials of the medium to be used for the primary test vials that were stored at room temperature between sampling periods. Each primary test vial had a total of five 4-mL aliquots withdrawn from it over the 168-hour study time period, thereby transferring all of the potentially exposed culture medium to the IV bags for sterility testing. Each withdrawal was transferred via the PhaSeal system under test to a separate 100-mL IV bag of TSB using the PhaSeal Infusion Adapter on the bag to provide a completely closed transfer mechanism, unlike the first study, which required the system to be “opened” to procure a subculture sample for sterility testing. Each institution received 415 bags of TSB for this purpose.

Individual 4-mL aliquots withdrawn from the primary test vial and transferred to an identically numbered and dated IV bag totaled 83 per withdrawal test day per institution. The first withdrawal followed the application of the PhaSeal Protector device to the 20-mL vial of TSB. That point in time was identified as hour 0; subsequent withdrawals and transfers to the next sets of bags occurred at 24 hours, 48 hours, 72 hours, and 168 hours. In all, 4 participating institutions each completed 415 total transfers, 83 per sampling session over the 7-day study period.

The IV bags prepared each day in the pharmacy were individually packaged in foil-coated, insulated bubble pouches and boxed for overnight courier delivery to the laboratory for incubation and monitoring under controlled and microbiologically optimized conditions. Upon receipt, IV bag samples were examined initially for visible growth and then held under controlled incubation at 35oC ± 1oC for 14 days. The bags were examined for microbial growth daily for the first 7 days and a minimum of 2 times during the 8th to the 14th day of the incubation period. One IV bag of 1660 total test samples showed visible contamination at 48 hours of incubation. That test medium sample had been drawn and transferred to its IV bag during a 24-hour sampling session. The 0 hour and subsequent IV bags (ie, hours 72, 96, and 168) of the same sample number all tested negative for contamination. The primary vial number 93 was lost or accidentally discarded after the 0-hour withdrawal from it; therefore, no IV bag samples were submitted for testing after hour 0 for sample number 93. Intravenous bag sample number 181 for the 48-hour draw was removed from the data set due to accidental exposure of the medium in the laboratory after 72 hours of incubation without showing any indication of microbial growth.

The on-site test protocol utilizing the PhaSeal system precluded sanitization of septa and connection interfaces other than the septa of the primary test vials and the rims of the IV bags’ spike ports, following the removal of their protective caps.

All containers of the culture medium used in the study were initially quarantined for 14 days at room temperature, and tested for growth potential with American Type Culture Collection (ATCC)-defined organisms, per USP requirement. Prior to distribution to the participating institutions, all containers of culture medium, including extra growth study samples, were preincubated at 35oC for an additional 14 days. Following preincubation of the IV bags, including 25 quality care samples for each participating institution, each set of 25 positive control test bags was inoculated with low concentrations of ATCC quality control microorganisms to verify continued growth support potential. The low concentrations of test organisms were prepared through serial dilutions of ATCC licensed product supplied by Microbiologics, Inc. Each set of 25 pretest quality care bags was divided into 5 groups of 5 bags, and each group of 5 bags was inoculated with a different one of the 5 organisms listed in 

. Final concentrations of the quality control organisms prepared through serial dilutions were approximately 0.5 colony forming units (CFUs) per mL. Actual concentrations are tabulated below. All pretest growth study samples were visibly positive within 48 hours of incubation at 35oC.

Microbial growth potential of the medium in the IV bags returned to the laboratory from the test sites was also verified by inoculating 25 bags from each participating institution with low concentrations of ATCC quality control organisms. Table 1 defines the organisms used and indicates the final average concentration of test organisms in the 100-mL IV bags inoculated for quality assurance testing in this study. A computerized randomnumber generation system was utilized to identify 100 IV bags (6%) from the 1660 total to be inoculated with the ATCC quality control microorganisms following their use and extended incubation. One bag was selected from each daily preparation set of 83 bags for each of the 5 quality control organisms. The test organisms were reconstituted, serially diluted, and inoculated into their respective IV bags within 30 minutes of rehydration to provide a final concentration per bag of approximately 0.5 CFU per mL. All posttest growth study samples were visibly positive within 48 hours of incubation at 35oC.

The analytic plan of this study was designed to answer 2 primary questions and was identical to the plan of the first study. The first question is, given the parameters of the study, would the CSTD maintain the sterility of the product such that the proportion of samples collected would have a proportion of failures (confirmed bacterial growth) no greater than the proportion of failures due to chance? Second, if sterility can be maintained, how long is it possible to keep the vial in use?

In this follow-up study, we benefited greatly from the prior work in that we had a more precise estimate of the actual proportion of failures. The failure rate in the first study was 1.8% of the tested samples. Therefore, we were able to design the sampling plan around an estimated null proportion of 2% rather than the 5% estimate we used previously. The sampling plan was then implemented to be able to answer the primary question with a 99% (± 3%) confidence level. Originally, the sample design was powered at 0.80. However, the final sample size (n = 331) yielded a post hoc power of 0.921. The increase in power despite the lower-than-designed sample size was due to the rather large effect size observed from the testing.

Results of the microbiologic analysis provided the answer to the first question. Although a total of 1700 samples were tested, the original sample (n = 331) provided the denominator for the test. The resulting failure rate of 0.3% (1 failure out of 331 samples) (99% confidence interval 0.0%-1.0%; 

 <.001) demonstrated that the observed failure rate was significantly different from the hypothesized rate of 2%. Therefore, we can be highly confident that the CSTD system was capable of maintaining sterility in a controlled environment. Utilizing the information gained from the microbiologic testing, we ran a secondary analysis of the data based on time to failure. In this case, a Kaplan-Meier

 univariate survival analysis was run using the PROC LIFETEST procedure available in SAS 9.2 (SAS Institute Inc, Cary, North Carolina). Since the test procedures did not lend themselves to exact timing of the actual moment that the bacterial contamination occurred (nor is that a realistic possibility), the same algorithm described in our first study was applied to determine the cutoff time point for the Kaplan-Meier test (see reference 1).

The results indicated that at the 168-hour mark, there was a probability of failure of 0.3%. In other words, at 168 hours one would expect there to be a 99.7% probability that the vial would not be contaminated with bacterial growth if the same procedures were utilized under the same environmental conditions. The results are summarized in 

Similar to our conclusions from the first study, we found that the PhaSeal system was able to prevent the entry of contaminants into the vials and did maintain a sterile environment. Using IV bags of culture medium allowed for direct introduction of the total contents of the primary vials into the final containers via a closed system. This step eliminated external variables associated with the previous subculture process that were sources of potential contamination. Because vials were used in the first study, it was necessary to remove medium from the vials for subculturing to avoid the potential for false-negative sterility test results. That process in turn created what we thought were some false-positive sterility test results by exposing the culture medium to the environment outside of the CSTD under test. Repeated testing of the culture medium for continued growth support potential indicated that the possibility of false-negative results had been eliminated, which further supports the results. Our second study also corroborated the time extension analysis from our first study. In our second study there was a 99.7% probability of vial sterility at the 168-hour mark.

The standards set forth in USP <797> were established to provide guidelines to minimize the potential for contamination of compounded sterile products. USP <797> also allows for extending the BUD, provided objective data exist to support the extension. As a result, healthcare institutions can maximize cost savings by minimizing waste without compromising quality as set forth in USP <797>. The results of our studies have demonstrated that the use of the PhaSeal CSTD on single-use vials does create and maintain a closed environment that prevents the entry of contaminants into the system. This would allow for extending use of the vial beyond the USP <797> 6-hour standard. Therefore, the PhaSeal CSTD has the potential to provide significant reductions in waste of viable pharmaceuticals. Interestingly, in a study published in 

, Sanchez-Rubio obtained similar results using PhaSeal and bortezomib.

 This study demonstrated that the sterility of bortezomib could be maintained for at least 11 days.

It is important to note that the focus of these studies was on extending the BUD based on sterility data. How far the BUD can be extended also depends on the chemical or biologic stability of the product, which must be taken into consideration. Another factor to consider when implementing the drug vial optimization concept is financial and billing regulation compliance. Institutions must evaluate their own specific billing practices before implementing drug vial optimization in their setting. Because the billing of waste is possible through the use of the JW modifier,

 it is incumbent upon pharmacy managers to discuss and coordinate implementation of the drug vial optimization concept with their individual hospital finance departments. This discussion is imperative to ensure proper billing methodologies and prevent any unethical or fraudulent billing activities. Quantifying waste and its financial impact to an institution can be significant.

An in-depth audit of waste was conducted at the SwedishAmerican Regional Cancer Center in Rockford, Illinois, in 2010. The center was able to determine that approximately $1.2 million worth of savings would be realized by extending the BUD utilizing the drug vial optimization concept. With annual oncology spending of approximately $12 million, these savings are similar to other reported cost savings resulting from prevention of waste of chemically stable medications.

 Preventing this waste would have a considerable financial impact. Preventing waste has an even more significant impact on patient care given the supply issues for antineoplastic agents that have plagued the United States in recent years. Although antineoplastic agents have been disproportionately impacted by supply issues, non-antineoplastic agents have suffered from supply chain interruptions as well. The concept of drug vial optimization for reducing waste of these low-cost but critical medicines could be used to minimize negative patient outcomes associated with drug shortages. In particular, many of the electrolytes that are available in bulk single-dose vials could be given extended sterility dating using this concept.

Limitations of this study should be noted. The PhaSeal protectors were recapped during the study procedures using aseptic technique and sterile caps from other PhaSeal protectors. While this recapping was done to minimize variables in this study, it is not real-life practice and these sterile protector caps are not commercially available. Although we do not believe this recapping contributed to the negative culture results, it should be noted. Additionally, the same or a very limited number of personnel were used at each site to conduct the study, performing the aseptic transfers in the same or a very similar manner each time. However, in real life, operations vary among healthcare practices, with some having dedicated personnel to compound antineoplastic and hazardous agents.

Although CSTDs have traditionally been used to reduce healthcare workers’ exposure to hazardous substances, this study further demonstrates the PhaSeal system’s utility in expanding BUDs and therefore reducing waste of viable pharmaceuticals. Extending the BUD results in improvements in the supply chain, beneficial effects on the environment, and significant cost savings for the healthcare system.

The Phaseal closed-system transfer device can extend the beyond-use date of pharmaceuticals, thereby reducing waste.

Second Look at Utilization of a Closed-System Transfer Device (PhaSeal)

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.

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

Utility of the PhaSeal Closed System Drug Transfer Device

When talking about specialty pharmacy, I am reminded of the famous words of Supreme Court Justice Potter Stewart as he ruled on a 1964 obscenity case. Justice Stewart wrote in his short concurrence that hard-core 

.” The same may be said for specialty pharmacy.

Generally, specialty pharmacy programs are designed to address drugs and biologics that are high in cost and difficult to manage, and have challenging reimbursement issues. These products often are problematic from all perspectives, including those of manufacturers, prescribers, patients, pharmacies, and payers. Specialty pharmacy programs evolved to address these issues by focusing on improving the access, delivery, disease state management, and financial support associated with these agents. Originally, specialty pharmacy could best be defined as a “cottage industry” that sprang up to support pharmacy benefit managers (PBMs) as they struggled with the management of increasingly high-cost agents. However, over the past 20 years, specialty pharmacy has grown significantly and many observers feel that it now is “the next big thing.”

Speaking about the future of specialty pharmacy, Zach Gerger, PharmD, DO, President, The Pharmacy & Therapeutics Society, noted that “traditional methods of reimbursement and clinical decision making around specialty health products are not working, and together we need to define the new way forward” (Personal communication). Figures from the 

 indicate that in 2003 the specialty pharmacy industry had $40 billion in overall drug spending, which rose to $78 billion in 2008.

 That is a 95% growth rate in just 5 years, which is not surprising given the numbers and types of drugs and biologics coming into the marketplace. Currently, approximately 50% of all drugs approved by the US Food and Drug Administration fall into the specialty category, and the biologics’ share of the pharmaceutical market has moved from approximately 15% in 2005 to more than 21% in 2010. This growth also has been subject to a confluence of other market factors such as declining reimbursement rates, shifts in coverage from the medical to the pharmacy benefit, increasingly complex monitoring requirements, and much greater emphasis on cost control. These factors have contributed to the evolution of specialty pharmacy as a way to better manage these high-cost drugs.

The trend in specialty pharmacy is to include virtually any drugs/disease states that are high cost, with the current focus on management of high-cost disease states such as cancer, HIV/AIDS, rheumatoid arthritis, multiple sclerosis, hepatitis C, infertility, solid organ transplant, growth hormone deficiency, and Crohn’s disease.

The provision of specialty pharmacy programs is currently dominated by the PBM industry, with much of the business provided by their own specialty operations. However, with the rapid growth of specialty pharmacy, opportunities are available for other players to enter the market. Many large hospital organizations are successfully moving into this market. As integrated service delivery networks, many organizations provide home and clinic infusion services, retail pharmacy services, and extensive clinical pharmacist support for targeted disease state management initiatives. In addition, many hospitals now are exploring the opportunity to get into the insurance/PBM business themselves. Integration creates a comprehensive portfolio that allows effective delivery of specialty pharmacy services.

Mike Flagstad, RPh, MS, Chief Executive Officer of Visante Inc, an organization that provides consulting services to both the PBM and hospital markets, observes that “there is certainly a lot of growth and change in the specialty market, but more importantly, a lot of opportunity. We (Visante) are seeing increasing interest from hospitals in creating specialty pharmacy service lines, and our consultants have already helped hospitals to successfully do this in Michigan, Nebraska, Tennessee, Massachusetts, Utah, Indiana, and Mississippi. One of the primary areas where hospitals interested in entering this market need support is in the management of billing and reimbursement associated with specialty pharmacy. Although hospitals may be well positioned in terms of service delivery and disease state management, they typically are not providing the financial infrastructure to effectively support a full-scale specialty pharmacy program” (Personal communication).

Retail pharmacies also are becoming increasingly interested in expanding their specialty market presence. They have traditionally been very good at product distribution and control. The primary barrier to a successful specialty program has been the lack of clinical expertise to manage the patient and the disease state, which is not an insurmountable obstacle. There are excellent examples of retail pharmacies that started out with a focus on specific disease states that they could manage and then expanded their expertise to support patients with other diseases. Diplomat Specialty Pharmacy in Michigan, for example, started out with a limited focus but gradually built up the required expertise so that they now offer a wide array of specialty programs in multiple states. The larger retail chains also have been successful in providing specialty pharmacy programs. For example, CVS/Caremark provides support for multiple disease states and provides specialty pharmacy solutions from personalized patient support services to medication management programs for health plans.

At the same time, some trends point in the opposite direction. Many health plans have or are examining exclusive arrangements in their contracting for specialty pharmacy and are creating arrangements with a single specialty provider, effectively locking other potential service providers out of that market. Manufacturers also are driving consolidation for some drugs/disease states. They are concerned about contracting with a wide variety of providers as they strive to create more service continuity nationally, which limits access to some smaller service providers. Limited distribution networks for specialty products are particularly frustrating to hospital and retail providers. In an attempt to control both inventory and data, manufacturers may opt for a closed distribution system. The advent of programs such as risk evaluation and mitigation strategies, often associated with high-risk/high-cost drugs, has created the need for extra data collection. From the point of view of the manufacturers, limiting the distribution of drugs increases compliance and the consistency of data collection.

However you define specialty pharmacy, this market segment is rapidly expanding. There is tremendous change both in and around the market (ie, new drugs), particularly in oncology, personalized medicine and genomics, a more integrated approach to patient care with medical home and accountable care organizations, and integrated patient care facilitated by electronic health records. All this growth and change mean opportunity for players in the market such as hospitals/health systems, retail chains and community pharmacy providers, PBMs, and health plans. Specialty pharmacy is a microcosm of the entire American healthcare system. It is evolving and changing, and we will be reinventing it in the next 5 to 10 years. For anyone interested in specialty pharmacy, this is not a good time to be on the sidelines. Now is a good time to get in the game. 

Over the last 20 years, specialty pharmacy has grown and changed significantly to better manage high-cost drugs with challenging reimbursement issues.