NSF Health Sciences Medical Devices, which assists companies in navigating US and international regulatory hurdles from product inception through to marketing, discusses how to set up a dynamic sterilisation process to deal with a constantly changing manufacturing environment
It could be argued that the most important and challenging steps in the manufacture of medical devices are contamination control and sterilisation. There are several reasons why these steps must always be foremost in the minds of manufacturers, the first of which is that failure to adequately detect and eliminate bacterial loading at any point in the manufacturing process puts at risk the most important element of the bottom line: the safety of medical patients who can be infected through a device that is supposed to help them.
In recognition of the seriousness of this risk, producers of medical devices are required to meet regulatory compliance standards for contamination control during the manufacturing process. There are also strict regulations governing bioburden testing and industrial sterilisation after all the components have been assembled.
There is no ‘cookie-cutter’ formula for meeting these standards because each device presents its own challenges. So each manufacturer must devise its own protocol for carrying out bioburden testing, documentation and sterilisation.
Meanwhile, ISO 14644, which provides the worldwide standard for designing and validating controlled environments, is under review, with possible changes pending.1 Currently there is no industry-wide consensus on what level of environmental bioburden is acceptable, making validation a moving target.1
Bioburden refers to the level of microbiological contamination a device carries by the end of the manufacturing process. The contamination can originate from some or all of the following sources: raw materials, storage conditions, the manufacturing environment and cleanliness, manufacturing process steps and personnel.2
To pass the certification and validation processes for controlled environments as determined by the FDA and other regulatory bodies, a manufacturer must create an ongoing programme of frequent, well-documented bioburden testing. For medical devices made or used in the US, testing is governed by Title 21 of the Code of Federal Regulations (21CFR) and worldwide by ISO 11737.
Bioburden testing is performed before sterilisation, and results are used to establish parameters for an effective sterilisation process.3 In a perfect world, bioburden measurements should remain consistent over time. But the manufacturing environment for biomedical devices is extremely sensitive to the slightest variations in air ventilation, cleanroom staffing or a supplier, for example.
Seemingly insignificant and unintentional changes can cause a flux in the number and types of micro-organisms, making fluctuations in bioburden measurements more common than not.3 Each manufacturer must set up a sterilisation process that can accommodate these fluctuations so that the finished product can still conform to industry standards.
Figure 1: Risk in the manufacture and assembly phases
MEDTEC Europe presentation, 4th June 2014, Stuttgart, Germany
For this reason, collecting and analysing bioburden data at regular intervals provides a reliable way to monitor the effectiveness of the contamination prevention process. If testing indicates that there has been a microbiological excursion during the manufacturing process, the source(s) must be found and eliminated immediately, before the anomaly causes interruption in the manufacturing process and deliveries to customers. Any variance necessitates the re-sterilisation and re-testing of contaminated product still stored on-site.
If the problem goes unaddressed for too long, the manufacturer will be forced to carry out a recall of contaminated product on the market or already in use – an expensive outcome both financially and in public relations terms.2
Exceeding the required level of testing and documentation not only makes good business sense – it also protects the company's certification and reputation
To prevent such a disastrous scenario, exceeding the required level of testing and documentation not only makes good business sense – it also protects the company’s certification and reputation. To comply with the standard, ISO 13485 Medical devices – Quality management systems – Requirements for regulatory purposes, all non-conformances must be investigated, and this includes bioburden results. Data from such investigations must be made available to regulatory authorities during an audit. If something does go wrong with a batch of product, and there is an audit, it reflects well on a manufacturer when it can demonstrate that records have been kept in good order, in a systematic way. Establishing and documenting a regimen of routine sterilisation testing is also a key piece of any quality assurance programme.3
It is helpful to consider that the responsibility for maintaining a sterile manufacturing environment is not just that of the sterilisation staff or quality control. Contamination can be introduced from any and all of the different stages of production (see Figures 1-3), and so it can be helpful to create a culture where all employees are encouraged to look for ways to constantly improve contamination control.
It can be difficult for many non-scientists to envision what is going on at a microscopic level, so a general microbiology training course can help raise the awareness of operators, technicians, and others whose duties may bring them into controlled environments.2 Learning more about the dynamics and difficulty of the battle against micro-organisms can help them take much more interest in the fight.
Figure 2: Risk in the design phase
MEDTEC Europe presentation, 4th June 2014, Stuttgart, Germany
Risk management is not a single activity, it is a continually evolving process carried out over the entire product life cycle. Tracking down and eliminating the sources of excursions may require the creation of a multidisciplinary task force assigned to spearhead such investigations. By meeting regularly to constantly tweak the contamination control, bioburden testing, and sterilisation systems, and by sharing perspectives on threats and successes, the group will be much more ready and able to handle a major problem if and when one develops.
In addition to providing a tool for determining if a microbiological excursion has taken place, data from bioburden testing also provides clues about the source of the contamination. For example, the presence of Staphylococci or Micrococci indicates personnel contamination during handling. Gram negative micro-organisms indicate water-borne contamination. In addition to tracking down sources of contamination, such detailed, up-to-date information about systemic microbiological loading provides an invaluable way to evaluate and improve the overall effectiveness of the sterilisation process.
Microbiological characterisation of the product bioburden is an essential requirement of ISO 11737-1:2006 Sterilisation of medical devices – Microbiological methods – Part 1: Determination of a population of micro-organisms on products. The methods used to characterise the type of micro-organisms present on a medical device are listed in Table 1.2
|Table 1: Microbial characterisation methods|
|Use of selective culturing|
|Genetic sequence data|
The first three methods (staining properties, cell morphology and colony morphology) are easy, quick and inexpensive to perform within the microbiology laboratory, providing adequate determination of micro-organism identification to the genus or family level for routine bioburden testing. The three remaining microbial characterisation methods (use of selective culturing, biochemical properties and genetic sequence data) are more time-consuming, require specialist equipment or media and are therefore more expensive. However, they can determine the identification of the micro-organism to species or sub-species level, providing more detailed analysis. In general, genetic sequence data is of limited value to testing for medical devices.2
Figure 3: Risk in the design phase
MEDTEC Europe presentation, 4th June 2014, Stuttgart, Germany
If a single bioburden excursion issue is serious enough, or if a pattern of continual bioburden excursions develops, it may become necessary to raise a Corrective Action and Preventive Action (CAPA) and in turn may lead to the raising of formal notifications to the regulatory authorities. These agencies will then expect the manufacturer to investigate thoroughly and to design and carry out plans to address the excursion. Typically, a root cause cannot be identified,2 and the manufacturer will have to retool its contamination control process so that the newly discovered excursion is neutralised and quality standards are met. The investigation may also find that a supplier is the source of the contamination, in which case the part or raw material may need to be sterilised before entering the manufacturing stream.2 To note this activity may then potentially establish further risks to product and/or packaging integrity!
Bioburden testing and sterilisation work together as firewalls for quality control, protecting the customer from deficient and possibly harmful product. Once a device undergoes bioburden testing, data collection and documentation, it enters the final stage of manufacture – sterilisation. Because the sterilisation dose and method is preset by the manufacturer, it can only handle product within certain parameters of microbiological loading. If a bioburden test reveals that the microbiological loading exceeds the design capacity of the sterilisation process, the device cannot go to market.
A successful manufacturer will create a dynamic system of data sharing between the bioburden testing and sterilisation processes so that these aspects of quality control can make needed adjustments in response to the subtle fluctuations in bioloading that are inevitable in any sensitive biotech environment.
As medical devices and manufacturing processes become more complex, regulatory agencies are considering changes to certification requirements, making validation a moving target
In designing a sterilisation process, the goal is to match product to the most likely contamination scenarios as determined by careful risk analysis studies and data collection from early bioburden testing. Dose must anticipate and handle reasonable fluctuations in microbiological loading. The most common methods used by medical device manufacturers are: irradiation (gamma, electron beam, X-ray); ethylene oxide; steam (including air ballasted steam); and gas plasma, with gamma irradiation and ethylene oxide as the methods of choice.4
All sterilisation methods require validation to demonstrate process parameters with a specified load configuration, to ensure a minimum sterility assurance level (SAL) of 10-6 according to EN 556-1:2001 Requirements for medical devices to be designated Sterile – part 1: Requirements for terminally sterilised medical devices.
But as medical devices and manufacturing processes become more complex, regulatory agencies are considering changes to certification requirements, making validation a moving target. It is also becoming more expensive, and a single manufacturer may find it difficult to keep up with changes. A growing number of manufacturers, large and small, are hiring vendors to handle bioburden and sterilisation testing. This can improve confidence in product safety and speed up time to market and revenue.1 A thorough internal risk analysis programme must still be carried out at intervals to ensure conformity to contamination control protocol and ongoing environmental monitoring at all stages of the manufacturing process.
As the threat from so-called superbugs worsens even in developed nations, the biomedical industry must respond with ever more vigilance to protect people in healthcare settings. Establishing a hair-trigger bioburden testing system that provides swift warning of microbiological excursions goes a long way towards fulfilling this responsibility.
Even the most powerful, state-of-the-art, expensive sterilisation programme can be rendered useless without a carefully designed system for bioburden testing, documentation and data sharing.
1. Steven G. Richter, Medical Product Outsourcing, March 13, 2014
2. Tracy Rennison, Cleanroom Technology, Sept. 2013, p.15
3. Pascal Yvon, Medical Device Summit, December 6, 2009
4. Tracy Rennison, Cleanroom Technology, Sept. 2013, p16