Every medical device maker lives and dies (in business terms at least) by the quality, safety and effectiveness of its devices. One of the basic tenets within this is that, during manufacture, the device has been kept free of contamination and produced within a controlled, and controllable, environment.
Yet with devices becoming more sophisticated, sensitive and complex, and often having the potential to be damaged or degraded by conventional sterilisation processes, how device makers control and protect the environment in which they are manufacturing - how they maintain and develop appropriate 'clean room' processes in particular - is becoming more challenging. They are having to learn lessons from other industries, notably pharmaceuticals and electronics, about how to take a controlled environment within the manufacturing process to the next level.
"For the manufacturers of sterile devices, it has been a long-standing requirement that you have to have a controlled environment in which the devices are manufactured," concedes Eamonn Hoxey, vice-president of regulatory compliance for Johnson & Johnson's Medical Devices & Diagnostics companies.
"The manufacturers of products and devices are, by and large, faced with three sources of contamination: the environment, people and clothing. So there will normally be strict hygiene requirements and fitness-to-work requirements to ensure there is control of the materials going in.
"When we talk about environmental control, the way people and materials come into that environment is a key part. But we are also talking about things such as temperature, humidity and the air, especially whether there are likely to be any microorganisms or particulates within it. There can be microbiological contamination or bio-burden, so what regulators look for are assurances that the environment has stability," he adds.
"For example, if you are looking to filter the air, you need to make the air pressure on the inside higher than on the outside, so that any air leakage is always outwards, rather than inwards into the controlled environment. Filtering, done effectively, should also keep the particulates under control."
There may also be issues around control pre-sterilisation, so the cleaning process that devices being reprocessed have gone through will require validating, as well as the wider environment. It has been a requirement that there should be 'a controlled environment' since the 1980s; however, Hoxey points out that one challenge for device manufacturers from the regulatory perspective is that the level of control has never been specified in detail. There is also very little in the way of essential European requirements, although there are moves to create a more harmonised regulatory landscape.
The other big challenge is how the rapid march of innovation and technology is affecting this issue now, and how it will affect it in the future. One of the key trends within medical devices of the past few years has been a drift towards miniaturisation, with advances in areas such as nanotechnology and the emerging field of nanopiezotronics, where implantable devices are powered by a patient's biomechanical and biochemical energy, generated by heartbeat, blood flow or even breathing.
Similarly, we are seeing the development of many more implantable devices, such as implantable insulin pumps and drug pain pumps, where sterilisation issues are obviously important.
"We are seeing more combination devices coming onto the market, often made with high-tech materials where the manufacturer is looking to reduce the level of contamination prior to manufacture, which obviously means you can use sterilisation processes to minimise the complexity and expense of the manufacturing process," explains Hoxey.
"It may well also mean the treatment processes that are in place during manufacture need to be less extensive. This can be particularly important in combination devices where there are biologics or active ingredients involved. This means there is not only the potential for the mechanical side of the device to be degraded during any sterilisation process, but the active ingredients also. But if you are able to pre-treat the materials, that can make things simpler."
Another challenge is that developing and maintaining a much more controlled manufacturing environment inevitably costs more money, adding to the already considerable time-to-manufacture and R&D bill for device makers.
"What we are starting to see is device manufacturers putting in environmental control at the same levels of magnitude as we have seen for some time within the pharmaceutical industry," says Hoxey.
"This will often mean human operators are completely excluded from the environment. Having automated processes makes it much easier to ensure the process is isolated and that the environment, and any sterilisation processes, can be controlled.
"Often, the more people you have within the assembly process, the greater the chance of contamination. This also means that manufacturing conditions and sites become much more expensive to validate and maintain. But if you want to get these sorts of products to market, you really have no option.
"The aseptic manufacture of devices is becoming more common," he adds. "It is about combining sterile products with aseptic production and manufacturing processes. It is particularly prevalent within the area of combination products or devices, and those with biologically active materials, growth factors or drug coatings. There will be a whole class of products and devices that require this level of attention within the manufacturing environment. There will be a lot more of them in the coming years and, no doubt, new types of devices that are being thought of."
In the future, Hoxey believes that we could see advances in cell therapies being incorporated into medical device scaffolds and matrices in an aseptic way.
"The key is that manufacturers do not get complacent. Controlled environments for manufacturing have been around since the 1980s, but the sorts of devices and products coming through now have the potential to change things. The medical devices industry is going to have to look to the pharmaceutical industry for its example, and possibly the electronics industry too."
Hoxey adds that he also expects to see advances in the environmental control within the micro-electrical industry, too, and that device makers would be wise to keep an eye on best practice in that field.
"I suspect we will also see more collaboration, and even joint ventures, between device and pharmaceutical companies," he adds. "They may well become part of the same parent or umbrella organisation. There is also the option of outsourcing to tap into someone else's expertise.
"Some quite large pharmaceutical companies already contract out their manufacturing facilities. It may well be that we see more device manufacturers using the controlled environments that have already been developed in this way to help with their own development."
- A 'clean' environment is one where products are manufactured, normally by controlling the concentration of airborne particles (generated by people, processes, facilities and other equipment) to specified limits.
- By comparison a 'sterile' environment is one totally free from microorganisms and their spores.
- Controlling contamination is about control of the 'total environment', in other words air-flow rates, air direction, pressurisation, temperature and humidity.
- The cleaning process itself, as well as its effectiveness, may need to be validated.
- A new generation of complex, sensitive and sophisticated biomechanical, nano and implantable devices is making controlling the manufacturing environment more challenging for manufacturers.
- The challenges of the future could lead to more joint ventures, collaboration and knowledge-sharing with the pharmaceutical and electronics industries.