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Pharmaceutical Manufacturing and Packing Sourcer

Terminal Sterilisation

Mark Botting of Isotron Ltd examines the developments in the sterilisation of drugs, combination devices and the regulatory changes that affect them

The huge increase of more advanced drug delivery systems in recent years has meant that manufacturers and contract sterilisation providers are increasingly working together to find a satisfactory sterilisation option for these devices. This new generation of combination devices offer a unique challenge to all parties as the regulatory environment requires that they conform to both pharmaceutical and medical device standards for sterility assurance. The contract sterilisation industry has been able, in most cases, to adapt its processes to handle current requirements through the use of microbiological control and new sterilisation techniques such as the electron beam. However, regulatory changes are being looked at to make the process more adaptive going forward.


The pharmaceutical approach to understanding microbiological risk through quality risk management (QRM) and by using ultra-clean and consistent processes has stood the test of time while avoiding the need for terminal sterilisation. This approach has developed predominantly due to the issues associated with using the main industrial sterilisation techniques of gamma irradiation and ethylene oxide (EtO). These high-energy processes involve free radical production that has always caused problems with the efficacy of the drug. In the case of EtO, the addition of heat and steam, and residual safety concerns, has made this technique non-viable. However, terminal sterilisation using gamma irradiation has remained an option for pharmaceutical manufacturers and is still used in some rare cases.

Medical device manufacturers do not have the same issues as the pharmaceutical industry as the devices are normally manufactured using plastics, metals or materials that are easily adapted to terminal sterilisation. Sterility assurance is obviously still critical for this market and standards have been developed and unified over the last 30 years which outline clearly how conformance to medical device sterilisation standards can be achieved. The latest version of ISO11137: 2006 ‘Sterilisation of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilisation process for medical devices’ defines the requirement to conform to a sterility assurance level (SAL) of 10-6 using gamma and the microbiological tests necessary to achieve this.


The development of drug combination devices for complex diseases – for example implantable drug delivery systems such as drug eluting stents – offers challenges to manufacturers as to how to conform to both approaches. While pharmaceutical manufacturers can follow either path, the risk of infection from the device, plus the clearly defined requirement for terminal sterilisation of devices, has meant that regulatory bodies and manufacturers are increasingly looking for ways to terminally sterilise their combination devices.

Manufacturers and their sterilisation providers have developed a number of approaches over the last 10 years that aim to sterilise devices without affecting efficacy adversely. These include:

  • Reduced irradiation dose (exposure) due to clean manufacturing
  • Electron beam processing
  • Temperature control and inert atmospheres


Historically, contract irradiation plants have processed medical devices at dose ranges of 25 to 40 kilograys (kGy) in line with the medical device requirements set out by the industry and the Association for the Advancement of Medical Instrumentation (AAMI) in the 1970s. Over the last 15 years, the development of the ISO11137 outlining the requirement to undertake microbiological testing has opened the door for a reduction in processing doses. This standard allows devices with low bioburden to be sterilised by minimum processing doses of 15kGy, or even lower in some cases, and through regular auditing of bioburden. As such, the efficacy of the sterilisation dose can be maintained while still conforming to the standard.

In addition, the development of more flexible gamma plants, the profiling of cobalt irradiation dose patterns, the use of shielding and changes in how the product is presented to the plant all allow tight dose ranges and mean that maximum doses can be kept to around 25kGy or lower. This significant reduction of radiation exposure time from the traditional approach has allowed some products to be processed at ambient temperature using gamma.


In the last 20 years, the development of commercially viable 10 MeV sterilisation beams that are in significant use by the medical device industry has opened up new options for pharmaceutical manufacturers. The main advantage of this technique is that the time to apply the sterilisation dose is seconds, rather than the hours needed for gamma. This reduction in exposure time directly correlates to a reduction in free radical generation and the negative effects that this causes to drugs and medical plastics. The use of the electron beam for drug eluting stents has been common for many years and can also allow processing at the minimum 25kGy, even if microbiological levels do not allow dose reduction. In addition, the use of shielding, thin product target areas (pizza box shapes) and the orientation of products to the beam have allowed maximum doses to be controlled to levels of around 35 to 40kGy.


Even the slight increases in temperature during the use of gamma or the electron beam can cause degradation, so this needs to be checked during validation of the process. However, it has been proven that keeping the product at a reduced temperature through the use of dry ice during irradiation helps to protect the drugs from the effects of free radicals and dampens the chemical reactions this causes in the drug.

A major negative effect of gamma and electron beam sterilisation techniques is the production of the highly reactive compound ozone through ionisation of air. The use of sealed packaging filled with inert gases, such as nitrogen, stops or severely reduces the production of ozone in the proximity of the drug and reduces the damage to efficacy, even at doses of 25kGy using gamma.

A consideration to make with either of these techniques will be the control of packaging and shipping, the cost of manufacturing and the ability of the sterilisation provider to handle either low-temperature products or the risk of handling pressurised containers.

The uses of the methods outlined above have allowed combination devices to be manufactured and sterilised routinely for many years. However, the expected large increase in the use of these products over the next 20 years, along with the complexity of drugs and devices, have meant that manufacturers and contract sterilisers are looking for a new regulatory route to make terminal sterilisation easier to achieve.


The International Irradiation Association (iiA) has sponsored three workshops on drug combination devices held in San Diego, US in December 2006, Washington DC, US in June 2007 and London, UK in 2008. These workshops brought together experts in the field of medical device manufacturing, sterilisation, drug development and regulatory approval to review the technical and process challenges associated with drug-device combination products.

One major discussion was based on the fact that SAL levels of 10-3 or 10-4 are commonplace for vaccines and other pharmaceuticals produced by aseptic processing. This therefore opened up an opportunity for the industry to select the appropriate SAL for a healthcare product more scientifically rather than taking the arbitrary 10-6 currently used by the medical industry. This SAL of 10-6 is seen as overkill in some cases, rather than a level required for safe use.

The workshops managed to gain both industry and FDA support, and allowed the iiA to request the set-up of an AAMI working group (WG90) in June 2008 to look at the current regulatory standards for SAL, taking into account infection rates and patient outcomes. The working group is expected to report back its initial findings this year.


The development of drug combination devices that require terminal sterilisation has meant that the contract sterilisation industry has needed to develop new ways of processing drugs through the tight control of dose and bioburden, and electron beam and controlled packaging, without adversely affecting the efficacy of the drug. These techniques allow pharmaceutical manufacturers to routinely sterilise drug combination devices, as well as to terminally sterilise drugs if required. It is important that the manufacturer receives input from the contract steriliser at an early stage in development to ensure that the drug can be sterilised using an irradiation technique.

However, the contract sterilisation industry is aware that these techniques are not the only solution and are now working with manufacturers, notified bodies and the AAMI to look at ways to reduce the sterilisation dose further, through adapting the regulatory requirement for SAL to patient need, rather than using the arbitrary levels currently in place.

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Mark Botting is the UK Commercial Manager at Isotron Ltd, a division of Synergy Health. After graduating with a degree in Chemistry from Nottingham University, UK, Mark worked at Isotron for eight years in a number of sales, marketing and technical positions before leaving in 2006. He rejoined Isotron in 2008 as UK Sales Manager and, over the last 18 months, has also taken responsibility for the marketing and operational management of Isotron Laboratories. In between his two stints at Isotron, he worked for Kendle, a global CRO, as Business Development Manager, which involved selling clinical trial management solutions to the pharmaceutical and biotech industries. Mark also has an MBA from Oxford Business School.
Mark Botting
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