In cleanrooms in the fields of medicine, pharmaceutical manufacturing and medical technology, it is necessary to satisfy a plethora of requirements, all depending on the particular circumstances. These can be ‘ranked’ as follows: Medical products are typically manufactured in an environment corresponding to cleanroom class D and then sterilised, while pharmaceuticals requiring subsequent sterilisation are produced in an environment corresponding to cleanroom class C. Sterile, aseptic filling requires cleanroom class A; and, in keeping with the ‘onion principle’, this area must be surrounded by a cleanroom of class B.
Two primary criteria for a clean environment
Every cleanroom system must be adapted to suit the specific process. It is possible to work with clean workbenches, for example. Here, the desired level of purity might be achieved through such measures as the horizontal or vertical laminar flow of filtered air, or one can work using gloves in an isolator, i.e. a hermetically sealed glove-box. In this case, ampoules can be filled in sterile production lines, or both can be combined to create an isolator with various filling modules.
The two cleanliness criteria are compliance with the maximum permissible particle concentration and the maximum permissible micro-organism level, or more specifically, the number of colony-forming units (CFU). In the fields of medicine, pharmaceuticals and biotechnology, the latter value is significantly more important than it is in cleanrooms intended for the production of semiconductors, for example. The CFU value is generally determined by taking a sample and placing it in a culture medium (usually an agar plate). One the sample has been cultivated, the number of colony-building units is counted.
Agar plates and fluorescence-assisted detection of airborne micro-organisms
When it comes to identifying/quantifying airborne molecular contamination (AMC), microbial air samplers are a particularly useful tool. These samplers collect the bacteria and fungus found in the ambient air on filters or directly on agar plates. Even so, it can take as long as five days’ cultivation before growth becomes visible on the plates (or plates cultivated from filters). A great deal can happen during this time, and it may even be necessary to dispose of entire batches. That is why a number of researchers have already developed processes that make it possible to immediately identify fluorescent molecules that could be indicative of the presence of micro-organisms.
Dr. Martin Klingmüller, Quality Manager at PNS GmbH, Melsungen and a specialist in the field of patient-specific parenteral nutrition, explains: “Today, there are systems that can identify cell wall components from bacteria and fungi in real time using florescence. However, these systems are still unable to distinguish between viable and non-viable components, which means that they cannot take the place of the colony-forming unit counts mandated by regulations.” In future, we expect real-time measurement methods to move ever closer to the capabilities required to satisfy pharmaceutical standards.
For heat-sensitive materials, transplants and grafts
Aseptic production is especially important for thermolabile substances (e.g. pharmaceutical agents) when is not possible to perform a final sterilisation using heat. This means that to prevent the entry of ambient micro-organisms, the environment in which manufacturing takes place must be practically free of micro-organisms, something that is achieved by the appropriate disinfection of the area, sterile tools and materials, and ventilating the area with air that has been filtered to the maximum possible degree (class A in accordance with EU-GMP).
Personalised medicine can result in even stricter requirements – it is one of the top themes of this year’s Cleanzone. Autologous tissue transplants are one such area – an example from the field of tissue engineering can be summarised as follows: The patient’s own cartilage cells are to be multiplied in the patient's own serum with the goal of creating cartilage cells that can be transplanted to replace tissue in the knee joint. The thermolabile transplant material is handled in an isolator corresponding to cleanroom class A. Thanks to a patented process, it is possible to carry out the glove change from the exterior room even while operations are ongoing – something that is also a major advantage in economic terms. Furthermore, this form of cartilage generation means that antibiotics and growth factors can be done away with entirely.
Particulate contamination increasingly important for point-of-care medical products
In addition to micro-biological contamination, particulate contamination is also becoming ever more important. Guido Kreck, Fraunhofer Institute for Manufacturing Engineering and Automation (IPA): “They are currently a major area of focus in the area of medical technology. If particles enter the bloodstream with an infusion, for example, they can cause thromboses.” Furthermore, the currently valid version of DIN EN ISO 13485 now mandates that particulate contamination be controlled for sterile medical products. Kreck: “In recent years this has led to us receiving an increasing number of enquiries here at IPA regarding how to deal with such requirements in actual practice.”
Another example is offered by implants, including dental and hip implants. Their surfaces are roughened to facilitate adhesion to the bone, a process known as osseointegration. Thanks to the fact that there is close contact with human tissue at the interface between the implant and the bone, it is essential that the product does not have any microbiological, particulate, chemical or film impurities, such as residues of auxiliary substances.
As a result, when manufacturing medical products it is imperative that a suitable and practical cleanliness concept be established, and that this concept account for the production environment (cleanroom, conventional production etc.), cleaning, production process, personnel and logistics.
Visitors to the Cleanzone trade fair will be able to experience all the latest trends in the fields of pharmaceuticals, biotechnology, medicine and medical technology on 23 and 24 October 2018 in Frankfurt am Main.
Press information and photographic material:
Background information on Messe Frankfurt
Messe Frankfurt is the world’s largest trade fair, congress and event organiser with its own exhibition grounds. With over 2,500* employees at some 30 locations, the company generates annual sales of around €661* million. Thanks to its far-reaching ties with the relevant sectors and to its international sales network, the Group looks after the business interests of its customers effectively. A comprehensive range of services – both onsite and online – ensures that customers worldwide enjoy consistently high quality and flexibility when planning, organising and running their events. The wide range of services includes renting exhibition grounds, trade fair construction and marketing, personnel and food services. With its headquarters in Frankfurt am Main, the company is owned by the City of Frankfurt (60 percent) and the State of Hesse (40 percent). *Preliminary figures for 2017
For more information, please visit the website at: