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Spick & span

urope’s current Medical Device Directive (MDD, 90/385/EEC) on active implantable medical devices states that, “devices must be designed and manufactured in such a way that, when implanted under the conditions and for the purposes laid down, their use does not compromise the clinical condition or the safety of patients.”

instance, if the implant is made of one solid polymer and can be autoclaved or gamma-sterilised, the required manufacturing conditions are relatively easy to specify.

The clear message here is on patient safety; however medical device manufacturers often struggle with the fact that the directive is not prescriptive enough in terms of the environment. Instead, some feel it leaves ambiguity over which clean manufacturing standard is applicable to their production environment specification and which guideline they should follow to mitigate risk. LIMITATIONS OF APPLICABLE GUIDELINES Typically, medical device manufacturing is conducted in ISO 14644-1:2015 classified cleanrooms, ranging from ISO 5 to 8, with final packaging usually conducted in an ISO 7 or 8 environment. This cleanroom standard however, does not provide specific instructions for medical device processes, and even ISO 13485 focuses mainly on the quality management systems throughout the life cycle of a medical device. This leaves manufacturers with quite a few questions to answer. What part of the product do we need to protect at what stage of manufacturing? Does it need post-processing and will the material or object withstand the conditions required? Does it need to be manufactured aseptically? How should it be packed and under which conditions?

But what if your active medical device is a polylactic acid-based absorbable implant? Sensitivity to hydrolysis and molecular weight reduction may not permit autoclaving or radiating. Post-sterilising the outer surface would also not be effective as, over time, the human body will be exposed to the core and the 3D printed inner layers of the object, including any potential contamination trapped in there during the manufacturing process. Trapped organisms could potentially be pathogenic or the core could be sterile, but still endotoxin-laden. So is ISO 5 sufficient, or should the manufacturing environment be scaled up to EU GMP A or B? EXPLORING NEW STERILE TECHNIQUES The question over sterile production and techniques has triggered researchers to start experimenting and exploring emerging technologies. It has recently been documented that 3D printing could be intrinsically sterile because of the temperature and pressure applied during manufacturing, such as in the article titled, ‘On the intrinsic sterility of 3D printing’ by Neches et al., 2016. In more than twenty incubations, the researchers found only two contaminated parts. Although the experiment was based on a limited amount of incubations and a rather wide spectrum of manufacturing conditions was applied, the researchers suggest that the printing process does indeed produce functionally sterile parts. Most of their experimental manufacturing conditions included the use of biosafety cabinets, including ultraviolet light, and aseptic preparation and decontamination of the printing area and substrate, and therefore, in essence, they were set up in line with EU GMP A particle and microbial manufacturing guidelines. From a clean manufacturing perspective, it was interesting to observe that the contamination on the parts was found to be common skin associated microflora, potentially indicating a post-processing handling error. Considering the latter, the results indicate that not only the technical (particulate) aspects of ISO 5 should be considered, but rather the whole chain of processing and handling activities should be defined in Standard Operating Procedures (SOPs) according to EU GMP aseptic processing.

What is needed in practice requires a thorough evaluation through risk assessments of the intended use, the class of the medical device, and its manufacturing materials. For


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