Over the past 40 years, there has been a significant change in how medical devices are manufactured, principally, from the use of metal and glass to medical grade polymers for single-use and disposable products. This shift, combined with more stringent regulations to more accurately address issues related to infection control, prompted the previous major change in sterilisation from steam autoclaving (often applied at the point of use, such as hospitals and doctors’ offices) to a requirement that products are delivered sterile by the manufacturer.
With continuing industry changes, including new regulatory initiatives such as Unique Device Identification (UDI), and additional cost pressures, such as the 2.3% medical device sales tax imposed by the Obama administration in the US, medical device manufacturing would benefit from a new approach to sterilisation that addresses manufacturers’ needs and fits with their workflow processes.
Medical devices must meet stringent regulatory requirements, such as ISO 13485 – which governs the manufacture of medical devices, including the requirements for medical devices to be designated sterile. Sterility is typically defined by demonstrating a reduction in the bacterial load to a Sterility Assurance Level (SAL) of Log 10-6.
Today, the majority of OEM medical device manufacturing sterilisation is performed on an outsourced, third-party basis, with approximately 53% of the market treated with Ethylene Oxide (ETO) gas sterilisation, and 43% using some form of ionising radiation (gamma, electron beam or high energy X-ray), and the remainder comprised of other methods, such as autoclaving, H2O2 gas and NO2 gas (see Figure 1).
This can vary quite considerably in different regions. For example, the UK market is heavily reliant on ionising radiation. China predominantly uses ETO; however, a large number of gamma facilities are being built, which will increase radiation sterilisation in that region. While the US is broadly in line with the global breakdown, this can vary regionally within the country, based in part on proximity to the third party service providers’ regional capabilities.
Ionising radiation and ETO sterilisation are capital intensive systems and, when transportation and logistics time is considered, sterilisation represents the largest single process step involved in getting the product manufactured and delivered to the point of care.
In the view of Steve Langron, Supply Chain Director of health technology consultants Lime Associates, the sterilisation process is often the longest step in the supply chain: ‘Outsourcing it has a number of operational disadvantages. The most obvious is the transport cost (and associated carbon emissions) to and from a sterilisation plant with annual journeys running into the hundreds for large plants and even small companies requiring a trip once a week at least. Typical cycle times from final manufacturing to availability for customer delivery is at least a week and is frequently longer, resulting in increased working capital requirements and longer customer lead times.’
Sterilisation options
Gamma irradiation was first used commercially for sterilising medical devices in 1963, and has been used effectively and safely for more than 50 years. The radiation source is typically Cobalt 60, which is manufactured in nuclear reactors by a limited number of entities worldwide. Lifecycle management of Cobalt-60 is an increasingly sensitive issue given both environmental and security concerns surrounding the handling of nuclear materials.
Ionising radiation sterilises by damaging the DNA and associated repair proteins of bacteria which may be present. Regulations for ionising radiation sterilisation are based on the dosage delivered, measured in kiloGrays (kGy), and the associated bioburden of the manufacturing environment in which the products are produced.
The alternative option, ETO, involves a toxic and carcinogenic chemical, which must be handled under very strict conditions to ensure the safety of workers managing the sterilisation process. The mechanism of action for ETO sterilisation is alkylations and/or oxidative reactions involving sulphydryl, amino, hydroxyl and carboxyl groups of proteins and imino groups of nucleic acids as well as cellular proteins. It is important to ensure that the de-gassing cycle has removed all of the chemical residue, and for certain valves fixtures and dialysis filter materials, ETO processing is not possible.
Other chemical processes such as hydrogen peroxide (H2O2) are also dangerous in the concentrations required to achieve sterilisation, and so impose strict health and safety compliance measures on the operators.
Regulations governing sterilisation of medical devices differ depending upon the sterilisation method employed. ISO 11137 sets out the guidelines for sterilising medical devices using ionising radiation, and ISO 11135 defines the sterilisation of medical devices with ETO. These standards, along with ISO 13485, have been adopted and implemented in all of the major medical device markets, enabling companies to manufacture in one market to their national standards and export and sell their products internationally.
| Table 1: Comparison of Cycle times & Compliance | |||||
| Sterilisation | Logistics | Total | Health & Safety | UDI | |
| Radiation | |||||
| Gamma | 10–20 hrs | 1–3 wks | High | High | Per pallet |
| HEXR | 2–8 hrs | 1–3 weeks | High | High | Per pallet |
| LEXR | <30 sec | None | Low | None expected | Per item |
| e-beam | <1 hr | 1–3 wks | High | Medium | Per box |
| Chemical | |||||
| ETO | 16–18 hrs | 1–2 wks | High | High | Per pallet |
| NO2 | 1–2 hrs | None | Low | High | Per box |
| H2O2 | 1–8 hrs | n/a | n/a | High | Per box |
| O3 | 5 hrs | n/a | n/a | High | Per box |
Recently, the US Food and Drug Administration’s (FDA’s) guidelines associated with UDI have been enacted. The UDI system consists of two core items: the first is a unique number assigned by the device manufacturer to the version or model of a device, called a unique device identifier. This identifier will also include production-specific information such as the product’s lot or batch number, expiration date, and manufacturing date when that information appears on the label; the second component is a publicly searchable database administered by the FDA, called the Global Unique Device Identification Database (GUDID) that will serve as a reference catalogue for every device with an identifier.
Compliance with UDI will be mandatory by September 2014 for Class III devices, followed by Class II devices by September 2016 and finally for some, but not all Class I devices by 2018.
Given the large scale batch processing associated with the existing methods of sterilisation, it will be difficult to gain the full benefits expected from the UDI system without an efficient method for individual item sterilisation and traceability.
In addition to the UDI initiative, since 1 January 2013, medical devices sold in the US have incurred a 2.3% sales tax to be paid by the companies selling the devices. Regardless of whether a product is manufactured in the US, if it is sold there, the tax is borne by the company selling the product. This is having a significant impact on the medical device industry.
This tax forms a key element of the funding for the Affordable Care Act, also known as ‘Obamacare’. Since the US represents approximately 50% of the US$300bn global medical device market, companies have had to accept it is here to stay. As a result, medical device manufacturers have placed a significant focus on cost reductions.
Figure 2: Polymer sterilisation – the radiation resistance of common polymers
Most medical grade polymers used today are well-suited to sterilisation using ionising radiation
The method by which a medical device is sterilised forms a part of its regulatory approval. If an external service provider has a problem, it is outside the direct control of the manufacturer; therefore, companies (and in turn their customers) must carry larger levels of inventory than if the process were within their direct control, or there were a back-up system available.
For example, last year, an electron beam facility in the UK had a fire, which put it out of operation for approximately three weeks. This directly affected all companies dependent upon that facility. They were also unable to switch service providers on a short term basis because of the time and costs associated with recertification. When issues arise in the centralised processing by third party providers, any delays must be borne by the manufacturers.
Meeting manufacturers' needs
Companies continuously seek process improvements and cost reductions, as well as competitive advantages in time to market. The last step of sterilisation is the only one outside of their control. Most manufacturers would prefer to manage sterilisation in house; however, as stated above, the capital costs associated with the current methods make it prohibitive, as well as additional health and safety requirements which would come with the existing methods.
When QA and RA managers from companies ranging from small, independent contract manufacturers to large global medical device manufacturers were asked if they could design their own sterilisation process what key features would they choose, they listed the following:
- Fully compliant with existing regulatory requirements
- Small footprint
- No additional compliance burdens
- Continuous monitoring of performance
- Lower cost
- Per item traceability
Future trends
In relation to chemical sterilisation, almost by definition, any form of new chemical sterilant, such as nitrogen dioxide (NO2), brings increased levels of regulatory compliance related to handling toxic chemicals in the workplace. Both Gamma and High Energy X-Ray (HEXR) radiation would impose significant health and safety compliance issues, assuming they were able to be implemented on site by medical device manufacturers. Today, no existing method of ionising radiation sterilisation could be justified for in-house use by any except a few of the largest medical device manufacturers.
NO2, H2O2 and ozone (O3) are seeking to make inroads on ETO’s dominant position in the chemical sterilisation market through companies such as Noxilizer and TSO3. NO2’s main advantage is that it becomes a gas at a lower temperature than ETO, and so is easier to implement. Although NO2 cycle times are shorter, as it is a non-traditional sterilisation method, the regulatory compliance issues are more cumbersome than for ETO. TSO3’s H2O2/O3 process is not yet approved for use, and is focused on the medical device reprocessing market.
Regarding ionising radiation, HEXR has been seeking to make inroads for some years; however, to date, its market share is estimated to be in the region of 2% worldwide. The lack of uptake is primarily because it is not substantially different from Gamma or E-beam – it is another large-scale, remote facility, which imposes the same logistical issues as the existing methods.
EnXray is pioneering a new approach to sterilising medical devices using Low Energy X-Ray (LEXR). The characteristics of LEXR make it suitable for individual sterilisation of medical devices for OEMs ‘on site and on demand’. LEXR is not able to transmit very far; however, the local absorption rate is very high, resulting in a high dose efficiency ratio. The intention is to provide a ‘matched kGy dosage’ to that achieved by the existing method (see Figure 3), to provide an alternative for sterilising rush orders or small batches more efficiently.
Figure 3: Comparison of LEXR and HEXR
The graph illustrates that EnXray technology delivers equivalent sterilising energy. The X-axis shows energy of X-rays generated on a log scale. The Y-axis indicates the level of energy absorbed by the target in Kilogray (kGY). EnXray is able to deliver the same amount of sterilising energy because of higher absorption rate of LEXR vs HEXR
The modular nature of the equipment is expected to enable easy integration into most manufacturing environments, allowing for ‘distributed sterilisation’ that will increase efficiency and shorten time to market for many companies.
In summary, with increasing regulatory pressures, combined with the need to identify cost-savings, terminal sterilisation is an area that will become more important in the future. With the advent of LEXR sterilisation, companies will be able to streamline their production processes, while lowering costs and improving time to market.
Figure 4: The EnXray prototype device for sterilising OEM medical devices based on initial concepts worked on with Cambridge Consultants
EnXray is a development-stage company founded in 2012 and focused on commercialising its patented and proprietary Low Energy X-Ray sterilisation technology. The technology has been demonstrated at an initial proof of concept level, and EnXray is developing its first fully functional prototype, expected in early 2015. The project is supported by funds from the UK Department for Business, Innovation & Skills under the Advanced Manufacturing Supply Chain Initiative.
