AAOS Bulletin - June, 2005

Seven simple questions to ask your tissue processor

By Michael J. Joyce, MD

The number of musculoskeletal allografts implanted annually has increased from approximately 350,000 in 1990 to more than 1,000,000 in 2004.1 To ensure the safety of these allografts, the Food and Drug Administration (FDA), supported by Congress and encouraged by the tissue banking industry, has finalized regulations on Current Good Tissue Practices (cGTPs). The final regulations became effective on May 25, 2005, and tissue processors/banks must implement procedures to meet the new requirements.

To ensure that your tissue processors are meeting the regulations for tissue procurement and processing, ask them the following questions:

1. What are your standard procedures for evaluating potential contaminants on incoming tissue?

Tissue recovery groups and processors procure tissue in a variety of environments, including operating rooms, medical examiner offices, morgues and funeral homes. The biological contamination or “bioburden” on these tissues can vary greatly depending upon the environment of the procurement setting, the circumstances surrounding the donor’s death and even the season of the year.

A tissue processor should have a validated system to assess both quantitative and qualitative aspects of any bacteria or fungi present in the tissue when it arrives at the processing facility. The tissue processor should have written policies to reduce the incoming bioburden, including standard operating procedures for donor preparation and tissue recovery practices.

2. What procedures do you use to detect microorganisms?

A tissue processor should have a multiple-step process to detect bacterial and fungal contamination present in donor tissues. Although surface swabbing has generally been considered the industry standard, this test is limited in its ability to detect microbial contamination. Ideally, tissue processors should employ a more sensitive assessment to test the entire surface area of the allograft whenever possible.

One example is the solution extraction method, in which the solution containing the allograft during transportation and/or processing is assayed for microcontamination. Destructive testing of companion tissue, while not adequate alone for the release of tissue, can provide an additional level of safety. An example of destructive testing would be grinding an accompanying representative sample of tissue from the donor for complete microbial culturing on appropriate media under appropriate conditions.

3. What in-process steps do you use to reduce the biological contamination of processed allografts?

In addition to using validated systems to detect microbial activity, a tissue processor should aim to eliminate contaminants within and upon the donor tissue. Even though complete elimination of contamination cannot be guaranteed, the tissue processor should validate the effectiveness of its decontamination or sterilization process by measuring its effects.

One method of representing sterility is the sterility assurance level (SAL). The SAL of 10-6 represents an assurance that there is a one in one-million likelihood that the graft is contaminated by bacteria. The medical device industry uses a standard SAL of 10-6 to represent sterile products, and it has been suggested that the tissue banking industry do the same for tissues labeled “sterile.”

The issue of sterility labeling for tissues deals more with the log reduction of bioburden and may not indicate the total absence of contaminants. The decontamination process should have the least deleterious effect on the structural integrity and biologic incorporation of the allograft. If used, terminal end “sterilization” by ethylene oxide, electronic-beam radiation or gamma radiation should be performed at levels that minimize effects on structural or biologic tissue integrity. In many cases, the sterility “assurance” on the label does not guarantee absolute absence of contamination.

4. Do medical professionals make the final determination on the release of allografts?

The decision to release an allograft for implantation is multifactorial and based upon information obtained through the donor’s medical and social history as well as serological testing and visual inspection. The ultimate decision to release the tissue for patient use should be based upon sound medical judgment. A tissue processor should employ a physician medical director whose job description includes reviewing donor social and medical histories, physical examination findings, pertinent documents and serology results, and giving final authorization before the tissue is released.

5. How do you address adverse event complaint reports from surgeons?

Immediate evaluation of adverse event complaints from surgeons is integral to ensuring continuing patient safety and quality assurance. Under the cGTP rules, surgeons are encouraged to report adverse reactions with human tissues to the source facility (the tissue processor).2 Tissue processor complaint systems must include a prompt response to reported adverse events and a thorough investigation that includes medical review of the case.

Tissue processors should require the quarantine and, if appropriate, recall of all tissues from donors whose tissue is associated with an identified contaminant. The tissue processor’s medical director should collaborate with the treating physician when investigating suspected cases of allograft infection. Additionally, tissue processors should have a formal process for implementing corrective actions when the cause of an adverse event identified from a complaint is attributable to tissue procurement or processing.

A tissue processor involved in the investigation of an adverse event should also report its final analysis, conclusion and any corrective steps taken to the treating physician. Prompt communication of these factors to transplanting surgeons is paramount in improving safety.

6. Are you in compliance with FDA regulations and accredited by the American Association of Tissue Banks (AATB)?

Now that the cGTP regulations are effective, the orthopaedic surgeon should ask the tissue processor if it is compliant. It is also helpful to ask if the facility has been recently inspected by the FDA, although FDA inspection is not a requirement of compliance. The cGTP rule will, however, strengthen FDA’s ability to conduct inspections of tissue facilities.

The AATB is the voluntary professional accrediting organization for the tissue banking industry. Although AATB is not a regulatory agency, it is a scientific, not-for-profit peer group organization that facilitates the provision of high quality transplantable human tissues in quantities sufficient to meet national needs. An AATB-accredited tissue processor undergoes a comprehensive on-site inspection every three years and has demonstrated that its procedures comply with both AATB standards and FDA regulations. Compliance with FDA regulations and AATB accreditation are important criteria to consider when choosing a tissue processor.

7. Does your serological evaluation of tissue include nucleic acid testing (NAT) for HIV and HCV?

NAT screening is a highly sensitive testing methodology that specifically evaluates the donor of allograft tissue for the genetic material of transmissible viruses such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The AATB now requires NAT screening for HIV and HCV with FDA-licensed tests for cadaveric blood for all tissue procured after March 9, 2005.3 NAT screening improves the safety margin of allografts by decreasing the “window” period when conventional antibody testing is unable to detect viral contaminants such as HIV and HCV. However, the final rule for cGTP does not address NAT as a requirement for cadaveric musculoskeletal donors, and the AATB standard does not require that tissues procured prior to March 9, 2005 and stored in inventory be NAT screened.

Summary

The FDA’s cGTP final rule requires significant changes in the tissue banking industry. It is imperative that practicing orthopaedic surgeons who work with allografts become knowledgeable about these regulations and, more importantly, become thoroughly familiar with the tissue processor that provides their allograft tissue.

Moreover, we as physicians must appreciate the altruistic decision by a donor or a donor’s family to provide tissue. Our patients’ lives are enriched by this ultimate act of generosity, and the medical community must respect the tissue as a gift and not just a commodity.

Michael J. Joyce, MD, an orthopaedic surgeon at the Cleveland Clinic, is past-president of the AATB, and a member of the AAOS Biological Implants Committee. He has consulted for the Musculoskeletal Transplant Foundation (MTF) and Cryolife. The author wishes to acknowledge the following for their contributions to this article: J. Robin de Andrade, MD, and David T. Curd, MS (Cryolife, Inc.); Lennox Archibald, MD (Regeneration Technologies, Inc.); David Gocke, MD (MTF); Alan Tillis, MD (Osteotech, Inc.); Tom Vangsness, MD (University of Southern California); Judith Woll, MD (Community Tissue Services), and Donna Toohey, staff liaison to the AAOS Biological Implants Committee.

1. American Association of Tissue Banks, Accredited Tissue Bank Annual Survey, http://www.aatb.org

2. An “adverse reaction” is a noxious and unintended response to any human cell, tissue, or cellular and tissue-based product for which there is a reasonable possibility that the product caused the response. See Food and Drug Administration Manual of Standard Operating Procedures and Policies: Procedures for Handling Adverse Reaction Reports Related to “361” Human Cells, Tissues, and Cellular and Tissue-Based Products. February 28, 2005.

3. AATB, Member Alert, Sept. 9, 2004, http://www.aatb.org.


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