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Good Tissue Bank Standards of Practice

What helps make a tissue bank good?

Following Standards of Practice (SOPs) in tissue banking is vital to ensure that every step of human tissue procurement, preparation, and distribution is held to the highest standards. This is done to ensure the safety, quality, and traceability of tissues for surgical use.

The internal Standards of Practice for tissue banks include documents that cover every aspect of this process. These standards cover topics including monitoring tissue recovery sites, the audit of tissue recovery partners, necessary body cooling protocols, microbiological surveillance programs, providing service to tissue donor families, prevention of contamination and cross-contamination at recovery, and many more.

However, the most relevant guide to understanding what makes a “good tissue bank” are the factors that govern “Good Tissue Practice,” defined by the steps that the FDA defines in the manufacturing of human allografts for surgical use: recovery, donor screening and testing, packaging, labeling, distribution, processing, and storage.1 Detailed guidelines for these areas of “Good Tissue Practice” have been developed by the national organization which audits and accredits participating US tissue banks.2

Recovery of Allografts

Recovery is the process of obtaining from a donor either cells or tissues that are intended for human use via implantation, transplantation, infusion, or transfer.1 It is the responsibility of the donor recovery agency to have a program in place that ensures donor information is received, investigated, evaluated, documented, and shared with all agencies that receive tissues from the donor to ensure donor suitability. There are specific SOPs in place to ensure that all recovery personnel are well trained and competent.

There are very specific steps that are taken by the donor recovery operation to control contamination and cross-contamination during retrieval. These steps include adherence to appropriate donor eligibility guidelines such as specific body cooling parameters and time limits for retrieval; ensuring a suitable location for recovery site activities; using clean techniques appropriate to the specific cells/tissues being recovered; cleaning, disinfecting, and sterilization of equipment, supplies, and instruments; monitoring recovery activities for microorganism contamination, such as by culture results; and sharing of all records related to donor eligibility determinations.

Donor Screening and Testing

The main step to prevent potential infectious diseases in the donor tissue supply is primary prevention, which comes from donor screening and testing, first in the form of the detailed medical-social interview (Donor Risk Assessment) of the donor and exhaustive review of their medical records and sexual history. There are multiple levels of review of every record, including by an independent medical doctor specializing in cytopathology. All tissues are also required to be tested by a range of FDA-licensed, cleared, or approved donor screening tests, as applicable by tissue type, such as for HIV, HBV, HCV, syphilis, HTLV, CMV, etc.3 Testing laboratories must also be registered as tissue establishments by the FDA, and are subject to the same rigorous oversight as tissue banks and procurement organizations.

Processing and Storage

Processing is defined by the FDA as “any activity performed on an HCT/P, other than recovery, donor screening, donor testing, storage, labeling, packaging, or distribution, such as testing for microorganisms, preparation, sterilization, steps to inactivate or remove adventitious agents, preservation for storage, and removal from storage.”4 Generally, processing includes cutting, grinding, shaping, culturing, enzymatic digestion, and decellularization of recovered tissues to make them suitable for surgical use.3 Processing must be conducted in a suitable clean room environment with appropriate environmental controls and monitoring.

Processing may also include a sterilization step such as gamma or e-beam radiation. Both are validated, controlled methods of improving allograft tissue safety. Most tissue banks employ a sterilization step in the face of infectious disease risks. To learn more about sterilization through radiation, see this post: Understanding Tissue Sterilization, Part 2: Radiation Round-up.”

Storage of allografts must be maintained at appropriate temperatures within each tissue’s tolerance limits. A temperature monitoring system must be in place to document storage temperatures and alert staff of deviations before straying outside of acceptable limits. Each unit of stored tissue should be packaged to facilitate sterile storage and prevent contamination or cross-contamination.

Packaging and Labeling

Packaging and shipping are not part of processing, and are therefore not required to be validated or verified in the same way as manufacturing. However, appropriate procedures must be in place to ensure the tissues are protected from contamination and cross-contamination, and that appropriate storage parameters are maintained during transport, particularly that temperature ranges are kept within acceptable limits.

Tissue labeling must make appropriate claims that are supported by verification and validation data to ensure that they are true and accurate. This could include information on sterilization procedures. Labeling also must include a method of internal donor identification, usually a lot-based identifying number on the label to allow for tracking and traceability of every tissue.

Distribution of Allografts

Strict regulations govern the transport and distribution of allografts, including an expiration date for their use. The expiration date is the maximum allowable storage period for the tissue, and expired tissues should not be transplanted. It is also critical to ensuring a safe allograft supply that the distribution of tissues be completely traceable from the original donor, to the retrieval agency, to the intermediary or processor, and on to any other tissue manufacturer or distributors to the ultimate end-user. The information that should travel with an allograft includes tissue ID numbers, tissue type, quantity, time of transport and delivery, recipient of delivery, and who transported and accepted tissues.

If you need help developing a tracking process for your surgical facility, there are resources available to guide you. In addition to the information above, a tissue tracking log should reflect the date of implantation and recipient of every graft. More information on tracking requirements can be found at the FDAs website .

 

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Hot Topics: Zika Virus and Allografts, Part 1

Background

Since the Zika outbreak first began in Brazil in late 2015,1 its spread has been of significant concern to the medical community. First identified due to the significant rise in microcephaly among newborns in Brazil, Zika infection has also been associated with other major birth defects including neural tube defects, eye abnormalities, brain abnormalities, and central nervous system dysfunction unrelated to microcephaly.

Studies have estimated the rate of birth defects among completed pregnancies with Zika infections to be 1 in 20, or 5%, with a higher risk of birth defects when infection occurs earlier in pregnancy.2 In addition to complications during pregnancy, Zika infection also has been shown to cause Guillain-Barré syndrome in adults and may result in other lasting neurological complications.3

Spread in the United States

The Zika virus is spread by two species of mosquito, Aedes albopictus and Aedes aegypti. Both of these vectors are native to the United States, but they are at the northernmost range of their territory and are therefore not found in every state. Ten states do not fall into the estimated range of either vector species and are therefore believed to be free of any native Zika transmission risk. The other states, as seen in the maps below, have at least small areas of potential mosquito transmission, though only Florida and Texas are known to have had local mosquito transmission of Zika to date.

Estimated range of Aedes albopictus and Aedes aegypti in the United States, CDC 2016*
*Maps are not meant to represent risk for spread of disease.

Zika became a nationally notifiable disease in 2016, which mandates reporting of cases to the CDC.4 As a result, there is very good surveillance of the disease in symptomatic patients, though many adults infected with Zika may remain asymptomatic or have only mild, flu-like symptoms.5

In 2016, the United States had 5,102 symptomatic cases of Zika reported to the CDC. Of these, only 224 were acquired through domestic mosquito-borne transmission (218 in Florida and 6 in Texas).4 There is a significantly declining prevalence of Zika virus disease in both North and South America, primarily due to the success of robust mosquito control measures and the public’s attention to preventing exposure.2

As of July 26, 2017, the United States has only had 181 symptomatic cases of Zika reported to the CDC for 2017. None were due to domestic transmission.6 It is believed that all prior areas of local mosquito transmission have been eliminated within the United States.

Clinical Testing for the Zika Virus

No diagnostic tests for the Zika virus are presently approved by the FDA for use in patients, though a number of tests have been developed. These tests are available due to an Emergency Use Authorization (EUA) for use in symptomatic patients residing in (or who have recently traveled to) an area with a risk of Zika infection. A total of 15 different tests are currently available under the Zika EUA, including molecular tests like real-time PCR and serological tests like ELISA. The Trioplex Real-Time RT-PCR assay (Nucleic Acid-based Testing) and the Zika MAC-ELISA (IgM antibody-based testing) are the only two tests that are in widespread use and distribution.7

Tests like these are important and clinically useful, but because of their newness and lack of FDA approval through the typical Premarket Application (PMA) process, concrete data on sensitivity, specificity, and predictive values are still being collected. Testing poses three primary challenges. First, the Zika virus is only transiently present in body fluids, which makes identifying the virus difficult using PCR NAT-based molecular testing. Second, serological testing for IgM antibodies using the MAC-ELISA cannot reliably pinpoint whether infection occurred during or prior to a pregnancy. Finally, serologic tests have been found to have cross-reactivity with other flaviviruses like dengue and are prone to false-positive results, which is a problem in zones where infection rates are high for the other flaviviruses.2

Current guidelines continue to recommend testing of symptomatic pregnant women with recent possible Zika exposure. However, the CDC now only recommends that asymptomatic pregnant women with ongoing possible Zika virus exposure be offered Zika virus NAT testing three times during pregnancy. IgM testing is no longer recommended for routine testing in pregnant women with ongoing Zika exposure, since IgM can persist for months after infection and therefore cannot reliably determine whether an infection occurred during the current pregnancy.2 The CDC also no longer recommends routine screening of asymptomatic pregnant women without ongoing Zika exposure, except in cases where prenatal ultrasound findings are consistent with congenital Zika virus syndrome to assist with establishing a diagnosis for the fetus.2

Testing for Zika in Human Allografts

Right now there is no test available to detect the Zika virus in human allografts, a category which includes placental tissues like the amniotic membrane and umbilical cord. The Procleix Zika Virus Assay is currently being tested under an Investigational New Drug (IND) protocol by manufacturer Gryfols and Hologic in conjunction with industry partners, but studies have not yet been completed to allow for FDA approval. The Procleix assay system, if proven effective, will be able to screen blood, plasma, and organ and tissue donations for the Zika virus.

You can read more about how tissue banks are managing risk for Zika virus in this blog post: Hot Topics: Zika Virus and Allografts, Part 2

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Hot Topics: Zika Virus and Allografts, Part 2

There is presently no test available to detect the presence of Zika virus in allograft tissues. This may change if the Procleix Zika Virus Assay now being investigated proves to be an accurate and reliable test. Until then, how are tissue banks managing the risks posed by this viral threat?

It’s important to understand that Zika is not the first virus to affect tissue banking, and the industry has specific protocols already established to protect the tissue supply. This begins with what happens before tissue procurement and acceptance, as the key to keeping Zika (and other viruses) out of the supply chain lies in primary prevention.

Tissue banks long ago implemented stringent donor screening methods and medical records review that form the basis of determining high risk for viruses such as HIV and hepatitis. These same screening methods are effective at assessing risk of Zika, along with other new contagious diseases such as West Nile, Dengue, and Chikungunya. Both deceased and living donors are screened for infectious disease risks routinely, although more public attention is focused on Zika at this time.

In the case of screening living donor mothers for Zika, Allografts.com owner Nikki Couloumbis turned to Craig Thomsen, the Director of Quality Systems for TissueTech, the Miami-based market-leading producer of cryopreserved placental tissues provided by Bio-Tissue and Amniox Medical.

Nikki: “Craig, can you discuss what TissueTech is doing to protect the placental tissue supply from Zika?”

Craig: “Absolutely. First, we do not work with any procurement partners that collect tissues within CDC-identified Zika transmission zones, including Miami-Dade, Broward, Palm Beach in Florida, and Brownsville, Texas. So, tissues potentially most at risk of infection are excluded, including the ones right in our backyard.

Second, we follow procedures that would disqualify outright those donors at risk of Zika. The main step to prevent potential infectious diseases has always been the Donor Risk Assessment Interview.”

Nikki: “In the case of deceased donors this interview is conducted with next-of-kin. But the same type of exhaustive review of risks is conducted with living donors. Can you explain some aspects of what you look for?”

Craig: “The DRAI is a very effective tool. It’s extremely in-depth, with very specific questions mandated by Federal and State authorities, supplemented by specific questions guided by company-specific exclusions. The interview addresses social behavior including drug and alcohol use, sexual partners, and tattoos and piercings. It includes a detailed family history, medical history, and travel history for the mother and her partner to known Zika transmission zones. Any living donor who has lived or traveled to an active Zika virus transmission zone within the last 16 months is not eligible to donate.”

“There are multiple levels of review of every record, including by an independent medical doctor specializing in cytopathology, and the exclusion criteria are very stringent, mandated by both the FDA and TissueTech Standards of Practice.”

Nikki: “I expect that in most cases, women at risk are self-identifying as well, so there is less likely to be a case that gets missed.  Furthermore, donors are uncompensated, so there is no incentive to donate if they pose a risk of transmitting Zika. Right?”

Craig: “That’s correct. The public’s high awareness of Zika makes it less likely that a tissue at risk will be donated to begin with. Donors with known infectious disease risks won’t be referred by their obstetricians for tissue donation, and pregnant women living in areas outside of transmission zones who believe they are at risk typically self-identify to their medical providers and request a test. This would be a part of their medical record, and it automatically excludes the mother from birth tissue donation.”

Nikki: “Clearly, it is highly unlikely that Zika-infected tissue will be processed with the extensive procedures that are in place. That’s good news. But let’s discuss your thoughts on sterilization methods. Irradiation has been used by some tissue banks to address concerns about other viruses in allografts.”

Craig: “While that is true, there is no validated method for destroying Zika virus in tissues. The amount of radiation required has not been quantified. So even radiated tissues would pose a risk if primary prevention procedures lapsed. And in the case of placental tissues, biologic value and quality would likely be affected. Truthfully, radiation is not necessary if strict exclusionary procedures are followed absolutely, and that is what we do at TissueTech.”

Nikki: “What is the news on a laboratory test for allografts down the road?”

Craig: “TissueTech has joined with leaders in the industry to jointly petition FDA to amend its recommended guidelines to include testing the donor mother’s blood as a screening tool. The FDA has already approved Zika blood tests for blood donation, so testing placenta donors would seem a logical extension of that. FDA has also approved an investigational study of an assay for Zika virus in tissues which would include placentas. So, yes, we expect progress this year and next year.”

Nikki: “Thanks, Craig, very informative. Our readers will appreciate your insights.”