Disclosure

Tammie Roy Chief Scientific Officer Genea Biomedx Sydney, AUSTRALIA

Declared to be employee of Genea Biomedx

Automation and standardization in embryology lab

Tammie Roy

Australia

1. Review the technology changes that have occurred in IVF

2. What automated equipment is available to the IVF laboratory

3. Understand Electronic witness and traceability technologies

4. Understand how automation and standardisation can improve IVF outcomes

5. Introduction to Automated vitrification

Objectives

What is Standardization?

• The process of implementing and developing technical standards. Standardization can help to maximize compatibility, interoperability, safety, repeatability, or quality.

• Can be achieved through: – QMS/QC systems

– Accreditation and documentation

– Education

– Automation

Why standardize IVF processes?

Number of ART cycles and outcomes reported in America (Centers for disease Control and Prevention 2013 report)

Laboratory Environment

Past Today

• Small room • Manual processes

• Controlled environment • VOC management • Clean room environment

Witnessing

IVF Witnessing is the process of ensuring that embryos, gametes and patients are handled and mixed correctly.

On average embryologist check up to 6 movements per cycle.

Some errors reported:

• Wrong sperm used for ICSI

• Affected weaker embryos transferred

• Wrong embryos thawed

• Embryos implanted in wrong patient

• Occurs <1% of the time (Thornhill, 2013)

Legislative requirements:

• UK HFEA Guidance Note 18 (mandated in 2004)

• Australia/NZ RTAC (initiated in 2011)

• US is under review.

Witnessing

Manual

“double checking performed on all clinical and laboratory procedures”

Issues with Manual double witnessing:

• Time consuming and distraction

• Signage paperwork required

• Variable reliability in technique

• Prone to human error

• Involuntary automaticity Errors can occur because staff saw what they “expected to see”

Electronic

• Utilises barcodes or RFID tags to identify and match samples

• Increased peace of mind for our staff and patients

• Risk mitigation and traceability

• Efficiency

IVF Culture Media

Past

• Individual clinics manufactured

• Non-defined ingredients used

• Variable across labs

• Use of cell culture media not developed for embryos

Today

• Commercially manufactured

• Defined ingredients e.g. HSA, Dipeptide Glutamine

• Quality controlled – Sterility

– MEA tested

– Endotoxin tested

• Additional supplements • Vitamins

• Growth factors

• Sequential and single step

Embryo Culture Environment

Large Box

• Slow Temp and CO2 recovery

• Large volume

• Temperature stratifications

Benchtop

• Quick recovery of Temp and CO2

• Smaller footprint

• Control and consistency of temp

Individual Patient Benchtop

• Optimal environment

• Controlled exposure

Embryo Selection

Subjective • Morphology

– single-point morphology is subjective

– low predictive value for embryo implantation potential

– relatively high inter-observer variability (even within the same centre)

(Braude 2013, Wang 2011).

Standardized • Timelapse

– Objective

– Uninterrupted culture

– Algorithms

• Pre-implantation genetic screening – Objective

• Mitochondrial analysis

• Proteomics

Cryopreservation

Slow Freezing

• Low cryoprotectants

• Controlled slow freezing rate

• Alignment of ice crystals to aid in damage prevention

Vitrification

• Higher cryoprotectant concentrations

• Rapid cooling and warming rates

• Prevention of ice crystal formation

• Improved embryo survival and outcomes

Automation

• Standardised

• Controlled variables

• Reduced learning curve

Why Automate Vitrification?

• Automate to attempt to control variables:

– Vitrification/warming solutions

• Cryopreservatives

• Sucrose v’s Trehalose

• Exposure

– Timing

– Temperature

– Device usability

– Open v’s Closed

Outcomes From Automated Vitrification

P-172 First pregnancies from human

embryos vitrified-warmed using the

semi-automated Gavi closed

vitrification system. ESHRE; 3-6 July

2016; Helsinki, Finland

Hobson, N.1; Filipovits, J.1; Roy, T. 2; Brandi, S.2; Woolcott, R.2; Bowman, M.1; McArthur, S.1

1.Genea Fertility, Sydney Australia 2. Genea Biomedx, Sydney Australia

Gavi Cryotop P value

Embryos vitrified 321 346

Maternal age

36.8

(33.9-39.6)

36.5

(33.9-39.4) .631

Embryos warmed 52 63

Embryo recovery

rate

100%

(52/52)

100%

(63/63) .999

Embryo survival

rate

100%

(52/52)

98.4%

(62/63) 1

Embryo transfers 52 62

Maternal age

35.9

(33.0-38.4)

35.4

(34.0-38.4) .512

Biochemical

pregnancy rate

65.4%

(34/52)

67.7%

(42/62) .791

Fetal heart

pregnancy rate

57.7%

(30/52)

58.1%

(36/62) 1

Subclinical

miscarriage rate

11.8%

(4/34)

14.3%

(6/42) 1

Implementing Automation

• Introducing automation into an IVF lab involves:

– Planning

– Training

– Assessment of workflows

– Lab restructure

– Evaluation of technology

– Ongoing monitoring

• Microfluidics – Embryo Culture

– Potential to allow culture from oocyte, through insemination and development (Han 2010 & Ma 2011, Swain 2013)

– Dynamic culture may improve development (Heo, 2010)

– Costs can be prohibitive

From: Ma et al, Anal. Chem., 2011, 83 (8), pp 2964–2970

From, Heo. Et al, Human Reproduction, Vol.25, No.3 pp. 613–622, 2010

IVF Laboratories of the Future

• Microfluidics – Sperm Preparations

– Can increase motility

– Reduced DNA fragmentation (Wasim, et al 2013)

– More efficient

IVF Laboratories of the Future

IVF Laboratories of the Future

• New dynamic culturing methods – Microfluidics – Co-culture – Next generation culture media

• Automated ICSI – Tested in animal models – 90% survival (Sun 2011)

• Real time measurements of embryo viability – Metabolism – mRNA

• Sperm Selection – New methods to identify and isolate most viable sperm

• Data mining – Personlised IVF

Take-home message

• The future is bright!!!

• Automation and standardisation will allow each step of the IVF process to be optimised resulting in a gold-standard of care and an overall increase in the take home baby rate from IVF.

Thank you