New requirements due to personalised medicine, real-time methods for determining micro-organism or hermetically sealed glove-boxes – find out more here about the cleanroom trends for modern medical technology.
Isolators are increasingly important in the pharmaceutical industry
SKAN specialises in the manufacture of isolators, and has played a key role in their development. In our interview, Richard Denk talks about the future of isolator technology and gives us a preview of his presentation at the Cleanzone Conference.
‘Isolators will continue to grow more important in the pharmaceutical industry, and there are two key factors for this. For one thing, there is a growing market for innovative biotechnology products, and thus for the sterile and aseptic environments in which they are produced.’
Mr. Denk, in what way has SKAN helped shape the development of isolators?
“SKAN has been manufacturing isolators for decades now, and it has been responsible for numerous scientific publications pertaining to aseptic production. In fact, this was a significant factor behind today’s use of isolators in aseptic production. Our publications are internationally recognised documents that are also cited in regulatory requirements for GMP.”
Is the importance of isolators increasing in the pharmaceutical industry, and if so, why?
“Isolators will continue to grow more important in the pharmaceutical industry, and there are two key factors for this. For one thing, there is a growing market for innovative biotechnology products, and thus for the sterile and aseptic environments in which they are produced. Regulatory authorities are increasingly mandating the use of isolators here, as this technology is considered to be one of the safest in the field of pharmaceutical manufacturing. Such requirements can also be found in the new draft of Annex 1 of the GMP Guidelines published at the end of 2017. For another, many of these new biotechnology substances are both highly active and extremely hazardous, and that means they require a high degree of protection for personnel. Furthermore, the requirements for employee protection are also rising in other areas, including the production of active ingredients and solid pharmaceuticals. Isolators are viewed as a reliable containment system here.”
How have isolator technology and containment developed in recent years, and in what areas do you expect innovations in future?
“As with any other field, it goes without saying that there will be innovations in the field of isolator technology in future. For instance, rapid product changes place huge demands on cleaning, and this is an area in which design and suitable decontamination procedures play a major role in isolator development. With our ‘VarioSys’ system, for example, we have developed a technology that allows pharmaceutical firms to fill vials in the morning, syringes in the afternoon and aseptic powders in the evening. This is all made possible by an innovative decontamination process that utilises an atomised solution of hydrogen peroxide (SKANFOG solution). The interiors of isolators will be increasingly automated in future, meaning that fewer interventions from outside using gloves will be required. Eventually there will be no need for any such interventions at all, thanks perhaps to the use of innovative handling systems or robots.”
As part of your presentation at Cleanzone, you will also be delving into the requirements for new pharmaceuticals, including antibiotics, highly active cytostatics, innovative new products such as ADCs (antibody-drug conjugates) and regenerative medicine. What does this mean for isolator technology, including with regard to cleaning?
“Cleaning requirements, particularly as they pertain to isolators, have been my concern for many years now, as isolators can generally be viewed as surfaces that do not come into contact with the product. In spite of this, to date there had been no threshold values for cleaning these surfaces based on the PDE (permitted daily exposure) as called for by the EMA (European Medicine Agency) since 2014 in the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.
To this end, in 2015 I established a group of international experts comprising GMP specialists, toxicologists and a GMP inspector with the aim of producing a publication offering descriptions of cleaning requirements on a sound scientific basis and a table listing cleaning requirements for surfaces that do not come into contact with products that is based on the PDE. This document was published in November 2017 by the PDA (Parenteral Drug Association) under the title ‘Isolator Surfaces and Contamination Risk to Personnel and Patient’.”
What is it that fascinates you about cleanroom technology?
“I’m fascinated by the manner in which cleanroom technology links the air quality that is required for safely producing pharmaceuticals with the process, cleaning requirements and the avoidance of cross-contamination, not to mention protection for employees and patients. And it’s all covered by an isolator solution. We live in a fantastic world in which we can look forward to a plethora of new medical products that will heal or even prevent illnesses in areas that appear impossible today. Anyone who would like to learn more about this topic should follow me on LinkedIn or come to my presentation at the Cleanzone Conference.
Germicidal surfaces, new systems engineering capabilities and innovative software for hygienic and efficient pharmaceutical production
Nikolaus Ferstl, Technical Director at University Hospital Regensburg, will be discussing ‘Innovations in the field of cleanroom technology’ and their importance for hospital operations at the Cleanzone Conference. He offers a preview of his presentation here in our interview.
‘University Hospital Regensburg operates cleanrooms in various areas, including the pharmacy, in the José-Carreras Centre for Somatic Cell Therapy, where it is used for the production of cell therapies and pharmaceuticals for Advanced Therapy Medicinal Products (ATMP), and in transfusion medicine.’
In what areas does University Hospital Regensburg operate cleanrooms?
“University Hospital Regensburg operates cleanrooms in various areas, including the pharmacy, in the José-Carreras Centre for Somatic Cell Therapy, where it is used for the production of cell therapies and pharmaceuticals for Advanced Therapy Medicinal Products (ATMP), and in transfusion medicine.”
What sort of investments are planned in cleanrooms over the next few years?
“In the field of cleanroom technology, we are investing in renewing our ventilation and air-conditioning systems, including the measurement and control technology, to satisfy hygiene requirements and reduce energy costs. We have also begun implementing a CATO project, and are in the process of creating the technical framework in which this can proceed. cato® is a comprehensive software solution for chemotherapy that supports the entire process, from long-term therapy planning and therapy support to the actual production of the cytotoxic drugs. State-of-the-art database technology allows for its utilisation both as a standalone application in smaller pharmacies, as well as in networks for large hospitals with station integration.”
With the growing number of multi-resistant germs in hospitals, what is the importance of cleanroom technology?
“Cleanroom technology has a huge role to play here. We are trying to deliver the necessary improvements in every area. These include the aforementioned new systems engineering capabilities, systematically structured quality improvements within the framework of re-validation and re-qualification activities / requirements, additional training for employees, and achievement of GMP production certification in all areas, including in production in pharmacies.”
Your presentation at the Cleanzone Congress is entitled ‘Innovations in the field of cleanroom technology’. Which innovations are particularly important for hospital operations, and what are some of the other factors that you will be addressing in your talk?
“The following innovations are particularly important for hospital operations: Hygienic and germicidal surfaces and materials, due to the high footfall, and the CATO solution I discussed, because it offers the potential for tremendous cost savings. Medications that have been opened do not have to be disposed of immediately, and can potentially be used for the preparation of medications for other customers. Other aspects of my presentation including current requirements mandated by law and GMP guidelines, while I will also be addressing the topics of digitisation, cleanroom technology 4.0 and BIM.”
The future belongs to real-time methods for determining micro-organism counts
Micro-organisms continue to pose new challenges for the cleanroom industry. Dr. Christian Raiss, Director of Testing Laboratory and Hospital Hygiene at the Hygiene-Institut AYSID GmbH, will be discussing the latest methods for determining micro-organism counts at the Cleanzone Conference 2018. He offers a preview of the topic here in our interview.
‘As the Director of Testing Laboratory and Hospital Hygiene, it is my responsibility to ensure that measurements and analyses of samples are performed in accordance with applicable standards and QM guidelines.’
Dr. Raiss, you are the Director of Testing Laboratory and Hospital Hygiene at the Hygiene-Institut AYSID GmbH. What types of tests and requests do you deal with in your everyday work?
“For one thing, our institute plays an active role in measuring and monitoring hygiene on site in both cleanrooms and hospitals. Our institute is also affiliated with a microbiological testing laboratory accredited by DAkkS, Germany’s national accreditation body. As the Director of Testing Laboratory and Hospital Hygiene, it is my responsibility to ensure that measurements and analyses of samples are performed in accordance with applicable standards and QM guidelines. I also provide expert consultation for planning and implementing construction projects in compliance with hygiene requirements.”
What topics will you be addressing at the Cleanzone Conference?
“I’m always fascinated by the ways in which micro-organisms manage to find entry into even the cleanest areas – and actually survive there. Even NASA must find and combat extremely resilient, hygiene-resistant bacteria in their cleanrooms. Finding, identifying and eliminating these micro-organisms, be they bacteria or mould, is an exciting job, and one that always confronts me with new challenges. Among other things, I’ll be taking advantage of Cleanzone to provide some tips on how companies can keep their cleanrooms sterile and combat contamination through the application of custom hygiene management.”
What is it that fascinates you about cleanroom and hygiene technology? What innovations in the field of determining micro-organism counts and cleanroom technology do you expect to see within the next few years?
“I always work to ensure that I’m up-to-date on the very latest technologies and processes, and I'm certain that real-time methods will be playing a major role in future. I’m fascinated by bio-microchips – some of these are even suitable for on-site use in real-time, providing readings directly without any need to send samples into the lab. Thanks to the fact that I’ve worked on these chips myself, however, I also know that it will still be some time before these innovative tools can be manufactured for a reasonable price. I will be delving into these and other themes, such as new methods for determining micro-organism counts, in greater detail my presentation.”
Micro-biological contamination poses the biggest challenge for manufacturing processes in the life sciences. Bioluminescence-based processes offer the potential to identify airborne micro-organisms faster in future – including real-time monitoring. Yet particulate contamination is also becoming increasingly important.
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.
The key feature of such procedures: With conventional optical particle counters, the system relies ‘solely’ on the Mie scattering when red laser light is shone on the particles and uses this to determine both the particle concentration and the particle size distribution. With florescence-assisted processes, a blue laser is used, and any particles containing fluorescent molecules absorb part of the laser light and emit it at a higher wavelength. Evaluating the data is a very complex process, as both the scattered light and florescence signal must be filtered out, and their intensities measured, in order to be able to estimate the viability of any micro-organisms found on the particles.
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.
Cleanroom technology: A key element for modern medical technology
Medical technology and cleanrooms are two sides of the same coin. In our interview, Professor Burkhard Stolz, Department Head and Course Advisor for Medical Technology at OTH – Technical University of Applied Sciences, Amberg-Weiden in Bavaria, discusses the importance of cleanrooms for his field.
‘In the medical and pharmaceutical fields, cleanroom technology has become an established part of the production environments that are essential to a wide range of products.’
Mr. Stolz, you are the Head of the Medical Technology Department. What is the importance of cleanroom technology to your course of studies?
Burkhard Stolz: “In the medical and pharmaceutical fields, cleanroom technology has become an established part of the production environments that are essential to a wide range of products. As a result, cleanroom technology is an important topic in both our bachelor’s and master’s degree programmes. Thanks to the fact that we operate an ISO class 7 cleanroom at the Weiden campus of OTH Amberg-Weiden, we are able not only to explain this technology to them, but to let them experience it for themselves. It is an opportunity that we take advantage up by offering a course of practical training in the bachelor’s programme. In the master’s programme, cleanroom technology forms an independent module that addresses both the theoretical and practical elements.”
What are the biggest challenges facing modern medical technology and what role does cleanroom technology have to play?
Burkhard Stolz: “Regulatory and quality requirements for medical products will only grow stricter in future, and that means that cleanroom technology will play a crucial role in ensuring product safety. These special production environments are very cost-intensive, so the focus will be on measures to reduce energy consumption. People will naturally continue to be active in cleanrooms as well. This is an area in which the training and qualifications of personnel play a major role, as does the production environment itself. The key will be to make working in a cleanroom attractive – by designing more appealing settings and providing better training in all areas.”
OTH Amberg-Weiden has already been an exhibitor at Cleanzone on multiple occasions. What is it about this trade fair that appeals to you?
Burkhard Stolz: “Cleanzone has established itself as an international meeting place for the industry in a central location that is an extremely good fit for the busy calendars of its visitors. I am very impressed by the event’s concept, which combines a trade fair with specialist presentations and various fields of communication. It offers something for established firms, as well as for newcomers to the field of cleanroom technology. We also appreciate the event’s professional planning and execution, as well as our good relationship with the trade fair team.”