Rachel Cutting, principal embryologist and quality manager at the Centre for Reproductive Medicine and Fertility Assisted Conception Unit, Sheffield Teaching Hospitals NHS Trust, explains what the EU Tissue Banking Directive and its adaptation by the Human Fertilisation and Embryology Authority (HFEA) means for IVF labs
For many labs, the deadline for the EU tissue banking directive may have passed, but for IVF labs this is not the case. From the outset, it was clear that the complex process of IVF could not be slotted into a simple process flow as with the manufacture of a pharmaceutical product. The raw ingredients for IVF are too unstable, and the processes involved too complex.
With this in mind, the rules have been relaxed somewhat to suit the circumstances of assistive reproduction: the directive has been adapted by the HFEA into more relaxed standards that are mandatory for clinics to meet.* However, since at Sheffield, we are allied to the University’s stem cell research groups, developing a cleanroom environ-ment was vital for us to be able to reach the standards suitable for ‘supernumerary’ embryos to be donated for use in stem cell research.
We were the first IVF lab in the UK to achieve cleanroom status. The journey was a long one, taking 12 months to adapt our working environment and practices, but it may be one that other labs can learn from.
The HFEA argues that insisting on more stringent regulations risks putting many of the smaller IVF labs out of business. Because it was not considered realistic to require grade A air quality, they recommended instead that IVF labs create a grade C environment in the flow hood with grade D in the background. It was felt that a compromise like this, while it still requires an immense amount of effort, is a workable solution that balances the cost and effort involved with the desired outcome.
At Sheffield, we had to set a higher target to comply with the regulations for stem cell groups. Compromises were made – for example, we have grade B air supply to our facility, we are wearing grade C clothing and paper notes are still used for witnessing. Yet even with this compromise, we are able to maintain a grade A environment within our flow hood.
The main concern at the outset was that patient treatment should not be compromised during the actual process of implementing the cleanroom technology: pregnancy rates had to remain stable throughout. To ensure this happened, during the six months we took to complete the process we had weekly design meetings with the cleanroom contractor and validation consultant. This meant potential problems could be overcome with solutions that would work within the particular constraints of an IVF lab – and that we could work towards the gold standard of Good Manufacturing Practice (GMP). We shut down for just two weeks to undergo a full validation of the new facility and equipment.
Planning was meticulous. At the outset, during the design stage, we made decisions on the grade of air within the facility and how we were going to achieve this. We had to really consider the process flow of all aspects of the IVF procedure, and we sat down with the contractors to draft specific plans for the movement of consumables, waste, samples, equipment and liquid nitrogen within the lab suite.
The last part of the pre-implementation stage was for me, as leader of the programme, to attend a Good Manu-facturing Practice course to learn how to manage the process of change effectively.
Once these steps had been taken, the actual business of changing the lab began – starting with the question of room function. We now have different labs for different functions. For example, since we need to get the eggs in the laboratory as quickly as possible after collection, the laboratory in which the embryos are stored is linked by a hatch to the theatre where the eggs are collected.
However, this hatch compromises the air pressure, so we have to ensure that the pressure within the lab is higher than in the theatre, which means that the air flows in the right direction – i.e. out of the embryo lab.
As well as changing rooms, we needed to invest in the technology necessary to maintain a cleanroom environment. To maintain a grade A environment in critical work areas, a flow cabinet with integral anti-vibration table was purchased for ICSI procedures. We developed key performance indicators and compared them with the 12 months prior to the changes, to ensure this new environment was not detrimental to the IVF procedure and outcomes. We invested in a dedicated filtered air system in the lab, and we have a computer-based system, from Facility Monitoring Systems, that continuously monitors everything in the lab – the freezers, the level of liquid nitrogen where embryo is frozen, the particle count on the hood and the air pressures in the rooms – to ensure that the environment is stable.
This final system has proved extremely useful as problems that may have previously gone undetected are now highlighted. For example, once the monitoring system was installed, we learned that an incubator would drift to different temperatures in the evening when no staff were present. Because we were alerted to it straight away, we could stabilise it, so providing a better environment for the embryos.
Storage of consumables was also an issue. Now, storage is limited within the suite and consumables are managed in a dedicated consumable prep room. All consumables packets are cleaned by wiping with alcohol prior to being taken in to the lab. We also needed to give the embryos the best chance of survival, so we use as many CE marked consumables as possible and a sequential culture medium, the Sydney IVF range from Cook Medical, to ensure that our eggs and embryos are provided with the correct nutrients they require to maintain viability and to that ensure our success rates are high.
Cleaning also had to be reviewed, both in terms of processes and cleaning materials. Again, this involved making compromises: in conventional cleanrooms, alcohol sprays and disinfectants are used to clean, but these chemicals can be harmful to embryos, so we use solutions that are friendlier to our environment.
Once we had changed solutions, we had to validate that cleaning was effective, so employed a microbiologist to test the environment. As consumable preparation and cleaning demanded increased time, we recruited a Medical Laboratory Assistant, who is responsible for cleaning and stock-taking.
Clothing was the final part of the process: to enhance the cleanliness of the environ-ment a three-stage clothing change system was introduced, with embryologists wearing cleanroom garments. Before, we simply put on a lab coat, but now we have blue under-garments and an overcoat, then hats, over-boots and gloves. These are put on in three stages, in three separate rooms, to ensure cleanroom standards are maintained. This rigour does mean that we have less face-to-face contact with patients, although we still update patients on the phone, so the effect is minimised.
Without doubt its was absolutely worth it. From the outset, there were concerns that IVF couldn’t be carried out in a cleanroom environment, as the air changes, silicon and treatments simply didn’t lend themselves to such a rigorously clean environment. In particular, questions had been raised previously raised as to whether ICSI can be performed within a flow hood. However, there has been no change in our (IVF/ICSI) key performance indicators, with fertilisation rates and clinical pregnancy rates being the same.
Obviously, one of the key objectives in undergoing such a time consuming and costly process was to be able to provide embryos to our colleagues in the stem cell research side. However, the stricter controls have improved the quality of our work within the lab. This has been borne out by an improvement in pregnancy rates, and by a stabilisation in pregnancy outcomes.
Adapting cleanroom technologies to an IVF lab can be done – and over time, I believe more labs will change to this environment. It is a question of putting the right technologies, controls and processes into place – from filtering systems to culture media. Anything that can be done to stabilise the environment within an IVF lab must have a positive effect. n