Variations in Allograft Sterility Levels: Understanding the Clinical and Economic Implication

By Angel Micarelli, Mark Moore, PhD, and Frederic Peycelon, MB

Introduction

As a leader in bio-implant technology and regenerative medicine, LifeNet Health bio-implants achieve the highest sterility assurance rating possible without compromising function or durability. With exceptional donor screening and stringent tissue processing techniques, LifeNet Health focuses on the safest product possible, while minimizing the economic impact of infections in the allograft market.

Differences and discrepancies exist between sterility requirements for medical devices and biotechnology supply organizations. But what many don’t realize is that the same sterility standards are not applied to organizations supplying bone and tissue allografts. One tissue supplier’s "STERILE" label may not carry the same assurance level as another’s, even though they both may claim sterility.

The implications of this variation are significant in terms of infection potential to allograft recipients and associated costs to the patient, hospital and health care provider. A recent study demonstrated that infections acquired through bacterial contamination of allografts have the potential to result in substantial complications or death.¹ The Centers for Disease Control (CDC) recently identified allograft-associated infection as a major public health risk.²

These grave clinical concerns are coupled with the significant financial impact of surgical site infections (SSI). In 2007, the Centers for Medicare and Medicaid Services (CMS) announced its decision to cease paying hospitals for some of the care made necessary by "preventable complications"—conditions that result from medical errors or improper care that can be reasonably averted.³The list of conditions targeted in this legislation was expanded in 2008 to include SSIs following certain elective procedures, including certain orthopedic surgeries. Considering the prevalent use of allografts in orthopedic reconstructive surgery, the connection is immediately clear: allograft-associated infections are within the CMS’s purview to scrutinize as preventable complications, and thus, non-reimbursable. Industry watchers see this change as the first in a series of anticipated CMS reforms of provider payment; hospitals may therefore view the new policy as a harbinger of things to come.³

These economic, clinical, legal and political factors combine to make allograft safety a serious risk management issue. Prevention is the key. However, unlike other infection control issues, preventive measures must begin long before the allograft reaches the clinician. Experts agree that one way to combat allograft-associated infections is to insist on rigorous screening, stringent aseptic tissue processing and sterilization procedures. Therefore, it is important to be able to trust the sterility processes used by tissue banks, as well as the donor acquisition Variations in Allograft Sterility Levels: Understanding the Clinical and Economic Implications

LifeNet Health, the leader in regenerative medicine, offers an innovative bio-implant technology that places the company at the forefront of higher sterility standards. Through its proprietary Allowash XG® sterilization process, LifeNet Health bio-implants achieve the highest sterility assurance rating possible without compromising function or durability. The LifeNet Health difference in sterility assurance can hold clinical and economic significance, as this paper will demonstrate.

Sources and impact of allograft infections

There are two principal ways by which allograft tissue can transmit disease: through an infected donor and contamination that occurs during tissue procurement, processing or packaging.⁴ During an eight-year Federal Drug Administration (FDA) study period of musculoskeletal allograft tissue recalls, 67% were attributed to improper donor evaluation and 21% were due to contamination (Table 1).^2,5

Donor screening and testing can reduce the probability of releasing tissue from a donor who has an active viral infection, but it has limitations during the window period when the donor does not have any detectable viral antibodies or antigens.⁴ Hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) have all been reported to have been transmitted by tissue transplantation.^6,7 However, improved screening tests such as Nucleic Acid Testing (NAT) have helped to reduce the risk (Table 2).

Federal and industry guidelines outline strict procedures for recovering donor tissue and bone. However, contamination can occur in normal processing and transferring of the allograft within a hospital or by health care personnel. Personal contaminants and human error have been the top two sources of contamination for the past 20 years.¹⁰

Economic implications: Eroding profits

An allograft-associated infection is defined as any surgical site infection at the site of allograft implantation occurring within 12 months of allograft implantation in an otherwise healthy patient with no known risk factors for SSI (e.g., diabetes).¹¹ Surgical site infections are the most costly for hospitals (Table 3). This directly impacts the hospital’s bottom line since SSIs are considered hospital-acquired infections (HAIs) (Table 4), which are no longer reimbursed by the CMS.

A study based on all the hospital infections reported in Pennsylvania in 2005 dramatizes this enormous economic burden: the average charge for patients who developed an infection ($173,206) was nearly four times as high as for patients admitted with the same diagnosis and severity of illness who did not contract an infection ($44,367).¹² Simply put, infections erode hospital profits.¹³ Further, there are potential legal ramifications. In a mock trial conducted by the American College of Surgeons, experts warned that "community standard of care" is an inadequate defense if hospitals and physicians fail to implement recently published, nationally available best practices with regard to infection control.¹³ Adhering to the highest standards for allograft safety will be more important than ever.

Health care providers and hospitals suffer loss of confidence and reputation. For patients, infection can be fatal, disabling or result in a lifetime of drug therapy. While the dollar range for an SSI is high, the total cost of infection transcends monetary figures.

In answer to the pressing issue of allograft-associated infections, the CDC issued a report in 2002 outlining the best way to reduce the transmission of infectious agents associated with allografts—new methods of sterilizing tissue that do not adversely affect the functioning of the tissue when transplanted into patients.¹⁵

Variations in sterilization techniques, levels and regulation

Just as there is no completely sterile surgery, there is no absolute sterile recovery of allograft tissue. Aseptically processed tissues are not classically considered "sterile" (defined as 100% free of pathogens). Aseptic processing alone does not reduce the inherent microbial bioburden present in donor tissue but only minimizes the risk of additional contamination. Due to the limitations of processing technology and environmental monitoring, aseptic processing does not eradicate microorganisms and spores, especially in tissue that is heavily contaminated at the time of recovery.^16,17

Numerous sterilants and sterilant combinations are used to eradicate microorganisms on allograft tissues (Table 5). These include chemical sterilants, gas plasma, ethylene oxide (EtO), gamma radiation and e-beam radiation as well as sterilization systems such as those developed by several allograft tissue processors. A 2006 survey of orthopedic surgeons found that 81% had some belief that tissue quality was compromised to some extent by sterilization processes.⁴

Variations in sterility levels: Heightening risks

The United States Pharmacopoeia (USP) has established standards for determining product sterility. A Sterility Assurance Level (SAL) of 10^-3 is comparable to the microbial survivor probability of aseptically produced products and is a level similar to the overall efficiency of an aseptic operation.⁴ This means there is a 1 in 1,000 probability of microbe survival.

Similarly, an SAL of 10^-6 means there is a 1 in 1,000,000 probability of microbe survival. In practical terms, there is a one thousand times greater risk of infection with an allograft with an SAL of 10^-3 than an SAL of 10^-6.

Tables 6 and 7 compare using an SAL of 10^-3 and an SAL of 10^-6 for 100, 250, 500 and 1,000 allografts per year. The expected yearly cost calculations assume a non-reimbursed cost of $25,000 per infection, based on the information presented in Table 3.

According to the Association for the Advancement of Medical Instrumentation (AAMI), the most rigorous terminal sterilization, during which both product and package are sterilized, is an SAL of 10^-6 recommended for invasive and surgically implanted medical devices. However, the FDA makes provisions for products unable to withstand terminal sterilization, such as allografts. If the product offers unique benefits for patient diagnosis, treatment or care, validated sterilization methods may be less rigorous—10^-5 , 10^-4 or 10^-3. The AAMI allows allografts produced by a validated aseptic process and that pass a validated sterility test to be labeled sterile with an SAL of 10^-3. Thus, meeting the AAMI guidelines for terminal sterilization (ANSI/AAMI/ISO 11137) that stipulate an SAL of 10^-6 is not required for tissue bank accreditation.

Survey data indicates that surgeons are generally confident in the oversight and regulatory guidance provided by the FDA and the American Association of Tissue Banks (AATB), a voluntary industry oversight and accreditation organization. However, they might be surprised to know that the FDA’s regulations in this industry are largely unfunded mandates, limiting the agency’s ability to enforce them. The AATB also issues specific guidelines for allograft donor screening, processing and sterilization. Member tissue banks are subject to inspection and audit every two years for accreditation renewal. About 2,300 banks are registered with the FDA but fewer than 100—around 4%—are accredited with the AATB.¹⁹ In 2005, the Department of Health and Human Services noted that only 13.7% of FDA-registered tissue banks had undergone FDA inspection.⁵ The reality is allograft tissue processing remains largely unencumbered by strict regulation for sterilization, secondary sterilization, chain of custody and procurement by either the FDA or AATB.¹⁹ This creates opportunities for unidentified quality control failure and increases the likelihood of serious infection from a single donor to be transmitted to multiple recipients. Costly infections can and do occur, even with increasing oversight and regulation. A number of the cases of reported infection involved FDA-registered, AATB-accredited tissue banks.

The highest level of sterility without compromising performance

Understanding the critical nature of allograft performance, LifeNet Health has made a commitment to achieve terminal sterilization of 10^-6 for most of its allografts. Using LifeNet Health’s patented Allowash XG technology, the investigators determined that terminal sterilization of 10^-6 could be achieved without compromising function or durability. (LifeNet Health bio-implants are labeled 99% contaminant-free, as the FDA does not allow any product to be labeled 100% contaminant-free.) A 2006 survey of orthopedic surgeons found that 81% had some belief that tissue quality was compromised to some extent by sterilization processes.⁴

Allowash XG sterilization process: minimizing risks without compromising quality

LifeNet Health’s proprietary and patented Allowash XG sterilization process provides an intense decontamination, disinfection and scrubbing regimen designed to remove and inactivate viruses and bacteria (Table 8). Donor tissue goes through a stringent screening routine and is recovered in strict aseptic conditions. Allograft bio-implants then go through serological testing to further control and eliminate incoming bioburden. The allograft bio-implants are processed and preserved in facilities that maintain cleanliness levels that minimize or eliminate environmentally induced graft contamination. Allograft bio-implants are cleaned with key solutions that are forced into and through the bone matrix and then directed to waste, resulting in the lysis of cells and cleaning of the tissues.

The decontamination, disinfection and cleaning regimens for the allograft bioimplants remove and eliminate viruses and bacteria. The final step is sterilization with a controlled and validated dose of gamma irradiation administered at low temperatures after the allograft bio-implant is packaged. As a result, LifeNet Health has achieved bio-implant sterility of SAL 10^-6 through a validated method that does not harm structural integrity or osteoinductive or osteoconductive potential.

Conclusion

The use of allograft tissue in musculoskeletal repair has been steadily increasing over the last decade as studies validate their biomechanical similarity to autograft tissue. While the incidence of contamination is reported to be infrequent, reporting systems likely underestimate the problem. It is not possible to determine the true incidence of disease transmission from allograft tissue because of the uncertainty of the exact number of allografts used annually in the United States and because of the possibility of inadequate detection of the pertinent infections (i.e., some postoperative infection may be presumed to be the result of intraoperative contamination) to the subsequent reporting of such infections.⁵ One thing is certain—the clinical and financial cost of even one infection is intolerably high. Infections acquired through bacterial contamination of allografts can result in substantial complications or death.¹ In economic terms, the impact is significant as well. Since allograftassociated infections are considered hospital-acquired, the related costs are not CMS-reimbursed. Those costs can range from $10,000 to over $30,000 per patient. Further, as guidelines become more stringent, hospitals may be held to a higher standard with the expectation that recently published, nationally available best practices must be implemented. If not, there could be further repercussions in terms of legal actions against both institutions and individual physicians.

Therefore, it is in the best interests of patients, hospitals and health care providers to be aware of all aspects surrounding allograft usage, including sterility. Understanding the processes involved in tissue and bone acquisition, sterilization and distribution gives clinicians the information needed to insist upon and use the highest quality bio-implant possible, case after case, patient after patient.

About Lifenet Health

LifeNet Health is the leading regenerative medicine company offering innovative bio-implant technology. Through its proprietary Allowash XG process, LifeNet Health bio-implants achieve the highest sterility assurance rating possible without compromising function or durability. Since 1995, LifeNet Health has delivered over 1.5 million allografts to the medical industry and no incident of disease transmission has been directly linked to tissue screened and processed by LifeNet Health. With exceptional donor screening and stringent tissue processing techniques, LifeNet Health focuses on the safest product possible every step of the way, while minimizing the economic impact of infections in the allograft market.

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Angel Micarelli is a senior medical science writer with Seidler Bernstein, Inc., a medical communications firm located in Cambridge, MA.