Unshackled- the new chain of Custody for the IVF industry.
“Chain of custody” is a step-by-step procedure that allows for identification of each and every person that handled sperm, oocytes and embryos and every step of the way during a patient’s IVF (or IUI) journey.
Long before egg retrieval and all the way to embryo freezing and storage ensuring traceability, accountability, security, safety and trust.
Cryostorage Problems – We should have seen this coming
It is hard to ignore the buzz around cryostorage in Assisted Reproduction now. It is a problem that we should have seen coming. Increasing demand for IVF, storage of gametes and embryos mounting up and our society becoming more mobile, more tech savvy, more informed
In our long career we have pondered about
● reducing the time spent auditing
● reducing time maintaining Liquid Nitrogen tanks
● shortcomings of searching for samples
● looking to improve the labelling system
Other industries in the biotech arena have passed us by with quality, facilities and cryo management much more advanced than our own.
It may be said that reproductive cells are unique in their requirements both biological and ethically. But cryo-biology is being used in other fields like our own e.g. in CAR-T cells with the same requirements for traceability, tracking, care and custody.
The growing success and need
With 1 in 7 couples searching for fertility solutions with IVF it is little wonder that the big boys of investment are involved now with global reach focusing on stored gametes and embryos.
To have safe, long term storage of cells it is important to have temperature uniformity when handling. New technology involving tags incorporated into consumables could help reduce current weaknesses.
By most measures the story of human oocytes and embryo storage/preservation as a technique in assisted reproduction is a success story. While established methods of cryopreservation for semen have been documented since the 1950’s and for human embryos from mid 80s.
In the last decade Vitrification has become the method of choice over slow rate freezing owing to improved post thaw/warm survival and pregnancy.
Vitrification is the snap freezing technique that literally plunges a sample into liquid nitrogen - avoiding the formation of ice crystals - and creating a glass like state.
UK’s HFEA, the watchdog of everything IVF, reports 11% increase in treatments with frozen embryos. Frozen Thaw Embryo Transfers are now comparable to fresh embryo transfer, and often achieve better clinical outcomes due to improved endometrial receptivity (23% Birth rate frozen vs 21% Fresh at time of writing). And with the ongoing trend in the USA for a preference of frozen-thaw embryo transfers over fresh – a quarter of all cycles are performed using the “freeze now - transfer later” motif.
Vitrification is also an integral part of PGD since biopsied embryos can be successfully frozen while genetic tests are being carried out.
And the excellent results of egg freezing heralds cryopreservation for fertility preservation whether for medical reasons (such as to avoid the effects of chemo and radiotherapy) or social freezing (where women want to defer starting a family till later).
One of the implications of this success is the growing inventory of cryo-preserved eggs, sperm and embryos and the need for safe and securely managed storage - short and long term.
Long term may be more important than short term, particularly with recent pressure in the UK for the HFEA to approve extended storage periods to account for changing lifestyle needs.
Current Status
But what is the big deal? - A very good summary of current status by acclaimed embryologist Mina Alikani in the Editorial in RBMO: “we need an overhaul!”
Late in the year 2018, we have seen 2 high profile Cryostorage disasters - two Dewar failures in two separate clinics in the same weekend in the USA.
There is a clear need for improved labelling, more robust quality management systems and risk management in an exponentially growing industry where more and more gametes are transported. Then there is a growing need for chain of custody, something absent in IVF labs but evident in most supermarkets today – all human food chains and pharmaceutical supply chains.
But there are problems inherent in current guidelines and practice. There is difficulty in monitoring, transporting and storing samples whilst maintaining optimum conditions.
The UK's HFEA requires clinics, at least once a year, to review the status of the frozen state (stored sample). Due to errors that dog our industry with serious consequences, witnessing is now an established part of IVF and mandatory in the UK.
But it is essential to prepare for the increase in storage management standards. The pressures are multi-faceted - fertility rates are dropping (obesity, environment and lifestyle changes chalking up problems for conception). Demand is growing and let’s not forget the value of the samples we are managing. Value to the clinic is 100% certainty of ID and procedural compliance: and emotional value to the patient.
With around 3,000 clinics globally and over 2.5 million cycles performed annually, this equates to a $16Bn industry in 2018 and predicted to increase by 10% (CAGR) per year with a worth of $39Bn by 2025 with about 21 million people having stored material (According to IVF tech company TMRW and others).
It is obvious that global mobility of samples and process conformity is needed as long as corporations are involved in swallowing up individual clinics and expanding globally and process, which was once the preserve of lone clinicians or a small group practice.
To reiterate the danger: yes there are dangers of Dewar failure or neglect (recent article of Dewar failure demonstrating there is 12 hours grace once seal failure begins- Pomerou 2019). But there are potentially greater opportunities for harm in the everyday practices. With more vitrification comes the possibility of damage from de-vitrification through not just mishandling but normal handling as you struggle to identify the sample.
Recent publications demonstrate the effects of sub optimum conditions for vitrified samples – especially as witness steps and auditing require removal of the samples from liquid nitrogen itself.
Macdonald has shown “real world” conditions of transporting gametes in vapour. While Ludo Parmegiani shows significant different survival rates of vitrified eggs using different modes of transport. Two more papers illustrate that glass transition ranged from the temperatures -126°C to -121° and potential premature warming at -121° could occur when checking samples at the Dewar mouth.
In the UK where it is mandatory for a second person to verify location of frozen samples and other steps and where it is mandatory that auditing be performed when removing samples from its immersed state We estimate that 8 witness steps are needed from the initial plunge into liquid nitrogen to warming again because there is no system capable of supporting this.
Risks:
Apart from acts of God - some risks can be predicted and avoided by following quality management, best practise guidelines and mandatory provisions provided by authorities such as the HFEA.
Highlighted by Tomlinson and Morol (first in an ACE survey in 2008 but several times since) there are possible risks to cryostorage such as loss or damage of stored material, misidentification or samples being used incorrectly:
Only 60% of clinics had steps to avoid thermal damage during auditing; 40% of clinics experienced illegible writing and 30% clinics have experienced missing samples; the audits show most errors in cryo-management are due to poor record keeping.
Dangers of such record keeping errors are prevalent in the news and headlined – often when a child is born of different ethnic origin (and therefore quite visible). While this is unacceptable and devastating to the family, to the embryologist involved it has both financial and legal consequences. But embryologists are human and have feelings too. They are equally affected by these errors as the families involved.
Although reported ART processing errors are rare, several technological solutions currently exist to safeguard against potential mismatches of patient’s gametes
The effectiveness of methods of human witnessing are debatable but incorporation of passive recognition and verification systems are paramount to patient confidence. Radio frequency identification is gathering in popularity.
But is double witnessing as effective as it should be? It was introduced as mandatory in the UK in 2002. Despite its apparent self-evident value, manual witnessing:
● is a burden
● increases the workload
● is susceptible to distractions
● adds more bureaucracy
● increases costs (particularly in “out of hours” procedures)
● and it may reduce effectiveness
The question of reduction of effectiveness is demonstrated when a procedure is performed repeatedly by the same person. The attention level decreases and goes into autopilot” or more correctly named “involuntary automaticity.” (See Toft and Masci-Taylor, 2005 - Involuntary automaticity: A work-system induced risk to safe health care.) Juran and Demming reported this in Total Quality Management studies in the car industry in the 1930s.
As a result, several alternatives have been trialled -Barcodes, ingenious silicon based microscopic barcodes (Novo, 2013) and systems based on radio frequency IDs.
Thornhill showed that the true mismatch in an IVF setting was .11% much better than other industries. [drug administration .2%, alarming 7-10% pathology labs and 0.8% input keyboard mistakes.]
“Surface tagging” in the lab is now commonplace where we mark every dish and tube with a unique tag so that if Mr Smith and Mrs Jones dishes come in close proximity then an alarm is triggered.
Until now no RFID tag could operate reliably at the low temperatures suitable for storage in liquid nitrogen. Here we describe a unique identification and audit system that can monitor position of individual frozen samples inside a Dewar of any type.
How it works:
A 2mm RFID tag fits to the end of (and is incorporated into) a handling device or straw or vial and uses radio waves of 13.56 MHz to transfer information. The copper coil provides power to the RFID tag which recognises changes in oscillations as messages.
Patient information is allocated (written) to the sample device by baptism via the i-ball – information such as name, patient number, colour of straw etc can be recorded.
The samples are then placed in a special canister inside a Dewar which wears a “necklace” The necklace around each Dewar neck acts as a reader (when samples go in) and acts as a transmitter to send the information along to the controller. The necklace can also be queried to “find Mrs. Smith’s samples” or to perform an audit on request. A typical audit of a Dewar takes seconds. The location of samples is enhanced by an LED on the necklace showing which canister contains the required sample.
Each component (the i-ball, device and necklace) can communicate with each other. All of this information is passed back to a controller.
The readers and controller can be linked to any device with Wi-fi such as a tablet or phone to read details of the freezing and storing devices and processes.
Everything is connected to the cloud through the controller and further connectivity to other clinics is possible giving true chain of custody and global visibility of clinical activity for the first time. (It is important to note that regulatory issues such as GDPR are considered in the system.)
Existing audit methods are laborious, time consuming with several shortcomings that have already been addressed. The use of Modified RFID (M-RFID) labelling would heighten security, safety and produce uninterrupted traceability. But data collection also enables other value add services, conferring additional benefits to the clinic.
The image below illustrates levels of visualisation. Liquid nitrogen Dewars and single canister’s content can be easily represented with clarity.
The images visualise a small 6 canister Dewar. Four of the canisters have material stored and two are empty.
The second diagram has “focused in” on position 2 and shows 3 differently coloured canes holding 2 yellow vials, 4 red vials and 4 green vials. This information is read live from within the Dewar.
We wished to undergo experiments where “real word” concerns could be addressed. These were presented at a recent conference (Palmer et al, 2019 -SLTB 2019) providing compelling evidence of proof that the Kustodian system can address Dewar storage shortcomings.
The experiments included
● 56 test cycles- imitating a tank audit
● 96 blind studies- representing misplaced samples,
● 44 cycles of absence of documented sample
A random number generator was used to define Patient MRN. Andrologist assigned the straw to the patient and a location was generated - again randomly.
A storage event was 1 cane with 3 straws.
31 mock patients were created; five patients had two freezing events to mimic the fact that many patients have stored samples on multiple occasions. There were a total of 108 tagged straws.
One further adaptation was added to represent real life storage facilities. We had two Dewars with 4 canisters each as choices for placement, not just a single Dewar.
Results showed that in 100% of samples
● all 56 test audits were located correctly
● immediate and accurate locations of the misplaced samples in blind and random redistribution events in all 96 samples was recorded
● Finally, there was immediate notification with the individual samples in the 44 cases where the samples were removed.
Early warning of a misplaced or missing sample would be very important to a clinic that would otherwise be under the false illusion/perception that the sample could be located quickly just prior to its use within the lab.
Conclusion
The growing cryostorage management issues show that it is time for a change. In order to reduce time spent in managing cryostorage, increasing reliability of labelling and reducing risks inherent in the current methods, this paper reports the research that has been undertaken to prove a new system introduced by Kustodian addresses all of these issues and opens up the capability of improved Cryostorage management. In a word Cryo Governance.
The work outlined demonstrates the proof of concept of the ability to use RFID tags as labels in liquid nitrogen storage tanks. The research demonstrates:
● samples are correctly recognised and read inside liquid nitrogen storage tanks
● Missing samples are quickly identified
● Sample location is clearly indicated
● Tank audit is simplified, and the audit time is reduced
● The approach reduces the potential exposure of samples to suboptimal conditions
● This removes the need for a second witness at a crucial time in storage and retrieval
And finally, it can be used for the first time true intra clinic chain of custody
By Giles Palmer and Peter Parker
Article from the talk:
Palmer GA, Parker PA, Dawson- Smith KJ, Igbokwe, NN. Improving sample identification and reducing risks during cryostorage of vitrified gametes and embryos using radio frequency identification (RFID) tags that operate while samples are immersed in liquid nitrogen., SLTB 2019 – Seville, 04 October 2019
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