Agnieszka Strabel
A manufacturer of medical devices produced using biotechnology faces numerous challenges arising from the specific nature of its device. However, by taking up the challenge of introducing and maintaining the device on the market, opportunities unattainable by others open up before the manufacturer, including the possibility of filling a market niche and making a real contribution to the development of science.
The article addresses the issue of risks associated with the production of medical devices manufactured using biotechnology, and also presents the opportunities that open up for the manufacturer.
It also contains practical guidance on meeting regulatory requirements.
Biotechnology is aimed at the application of biological processes in technological and production tasks. People used biotechnological solutions before they knew the principles of their operation. Traditional biotechnology makes use of the naturally occurring properties of organisms, which are provided with suitable conditions in order to obtain the desired product.
Modern biotechnology, on the other hand, also makes it possible to analyze them, modify them, and design their genetic material. For this purpose, techniques of genetic engineering, molecular biology, and cell and tissue techniques are used, as well as knowledge from many fields of science, which makes it possible to create breakthrough therapies, modern diagnostic tests and biomaterials.
Thus, according to the definition of the European Federation of Biotechnology, biotechnology is the integration of natural sciences and engineering sciences in order to use cells or their parts and molecular analogues to obtain products and services.
In industry, bacteria, viruses, animal and plant cells, extracellular substances or isolated cell components are used for production. The processes used are mainly the multiplication of cell mass, the production of metabolic products, or the application of reaction mechanisms. As knowledge develops, there is a gradual but systematic development of other biotechnological production processes as well [1].
MDR (Medical Device Regulation) is the EU Regulation of the European Parliament and of the Council (EU) 2017/745 of 5 April 2017, which introduces uniform rules concerning medical devices sold throughout the European Union. As is commonly known, in accordance with the content of the MDR Regulation, a medical device means an instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for at least one of the specific medical purposes listed in the Regulation, and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means [2].
What, then, are medical devices manufactured using biotechnology?
Medical devices manufactured using biotechnology are advanced products subject to EU regulations, such as the above-mentioned MDR Regulation (EU) 2017/745 or the Regulation on in vitro diagnostic medical devices IVDR (EU) 2017/746, depending on the device [2,3].
MDCG 2019-14 gives the following examples of processes which, when used in the manufacture of medical devices, qualify them as biotechnological devices. These are fermentation using cell cultures, enzymatic production processes, and the purification and modification of biomolecules [4].
Companies that carry out manufacturing activities and often, at the same time, research and development activities in the field of biotechnology encounter many challenges along the way, starting from the area of design, implementation into production, production itself, and distribution of the devices. The development time of this type of device itself may be extended, as it is subject to many factors.
Issues such as the type of product, the type of technology, the organization of production, the availability of raw materials, demand, or regulatory issues must be taken into account when operating in the biotechnology industry. Furthermore, as with all medical devices, the issues of the safety and effectiveness of the device for the user are extremely important.
Biotechnological processes differ from the classical chemical processes used in production. These differences consist, among other things, in the type of material we work with. During production, the complexity of the material, its possible variability over the course of the process, and its sensitivity to external factors must be taken into account. The issue of process requirements such as sterility or reproducibility is also very important. The production scale and the working volume of the bioreactors must also be considered. The process often runs differently on a laboratory scale, on a semi-technical scale, and differently during industrial production. Moreover, the course of the process is affected by complicated kinetics, the requirement for high precision in the regulation of bioprocess parameters, including the maintenance of temperature, pH, and substrate and product concentrations, inhibition of the process by metabolites, which must be removed from the reaction environment, the variability of biological material related to the growth and death of cells, morphological changes of organisms, variability of the environment, or the occurrence of unsteady, transient states [5].
Process costs, product purity, and production efficiency are also extremely important parameters. Therefore, knowledge from various fields of science, such as genetics, biochemistry, and process engineering, brings new, better and simpler techniques that allow the manufacturer's benefits to be maximized [1].
Medical devices manufactured using biotechnology are very often innovative devices, not previously present on the market. Therefore, it is first necessary to consider whether the product manufactured using biotechnological methods is a medical device and is subject to the MDR Regulation or other regulations, including those concerning medicinal products.
The European Pharmacopoeia deals broadly and in detail with issues of biotechnology and the products obtained by means of it. It regulates the quality requirements and specifies the degree of purity that biotechnological and biological products and advanced therapies must achieve in order to be used in humans. It contains general and specific monographs, specifies test methods, reagents and solutions, and packaging requirements, which may be useful for this type of device [6].
The manual Manual on Borderline and Classification under EU Regulations (EU) 2017/745 (MDR) and 2017/746 (IVDR), developed by the MDCG working group, contains explanations that can help during the qualification and classification of devices that are on the borderline between the MDR and other regulations [7].
It is also important that, when preparing the device documentation, the manufacturer pays attention to the correct classification of the device in accordance with the requirements of the Regulation of the European Parliament and of the Council (EU) 2017/745 of 5 April 2017, Annex VIII [2].
Correct classification is the basis for the further course of action taken by the manufacturer in order to meet regulatory requirements, and also constitutes the entry point into the assessment process.
The guide MDCG 2021-24 Rev.1 Guidance on classification of medical devices helps to assign the device to the appropriate risk class. It contains block diagrams and practical examples reflecting the rules under the MDR [8].
The essential requirements for medical devices indicate ways of designing and manufacturing them so that, during use, these devices do not endanger the health and safety of patients or healthcare workers. Furthermore, ISO standards help manufacturers control the risk of the device, maintain its consistent quality, and facilitate its introduction to markets around the world. These include, among others, the following standards:
- PN-EN ISO 13485:2016-04 Medical devices – Quality management systems – Requirements for regulatory purposes,
- PN-EN ISO 14971:2020-05 Medical devices – Application of risk management to medical devices,
- PN-EN 62366-1:2015-07 Medical devices – Part 1: Application of usability engineering to medical devices.
Many standards from the ISO 10993 family, which help in the biocompatibility assessment of medical devices, are also applied to this type of device, including the fundamental one:
- PN-EN ISO 10993-1:2026-06 Biological evaluation of medical devices – Part 1: Requirements and general principles for the assessment of biological safety within a risk management process [8].
It is also important to determine and carry out appropriate genotoxicity, carcinogenicity and reproductive toxicity tests, in vitro cytotoxicity tests, skin sensitization tests (if applicable), systemic toxicity tests, and irritation tests. The identification and quantitative determination of potential degradation products, as well as the chemical characterization of the materials of the medical device, are also important.
In addition to biocompatibility, particular attention should be paid to the stability of the device and its compatibility with other devices (if applicable), without forgetting a correctly and conscientiously conducted clinical evaluation.
Usually, the numerous studies carried out as part of validation, verification and testing cover, in addition to standard parameters, issues related to the use of alternative, innovative materials and substances, as well as packaging issues.
The stability of the device must be demonstrated, including the shelf life throughout the entire life cycle of the product. It is up to the manufacturer to choose the best method, with an indication toward combining different methods [2].
Tests are carried out under normal storage conditions. However, this is a lengthy method. Therefore, tests are also performed in which the products are exposed to higher-than-usual environmental stresses, including temperature and humidity, in order to speed up the time needed to obtain a result [1].
For devices manufactured using biotechnology that are used in combination with at least one other device and in accordance with its intended use, their mutual compatibility must be demonstrated. For this purpose, the manufacturer must prove their performance in accordance with the intended purpose without loss or impairment of capability, or the capability of integration and functioning without the need for modification and adaptation of any part of the connected devices. It is necessary to demonstrate the possibility of combined use without conflicts or interference and without adverse effects [2]. This is a requirement imposed on all devices compatible with other devices, but in the case of novel devices it may be exceptionally difficult.
In order to carry out a correct clinical evaluation, it is necessary to systematically and in a planned manner continuously generate, collect, analyze and evaluate clinical data relating to the device during use in accordance with the manufacturer's intended purpose, and to monitor the market. The manufacturer determines the scope of the clinical evaluation on the basis of the type, classification and intended use of its device, as well as information such as labeling, instructions for use and promotional materials, and the risks of its use [2].
In the case of innovative devices, a clinical evaluation of the device based on the clinical data of a device considered equivalent, based on a comparison of its technical and biological properties, is practically impossible, which also constitutes a major difficulty for the manufacturer. It is the manufacturer who is responsible for its correct planning and execution.
It is also worth remembering that the entire documentation should be reflected in, and consistent with, the label and instructions for use. Labeling should comply with the general requirements of the MDR and contain all elements, including those resulting from the characteristic specificity and hazards arising from the manufacture of medical devices using biotechnology. The markings used on medical devices are contained in the standard PN-EN ISO 15223-1:2022-01 Medical devices – Symbols to be used with information supplied by the manufacturer – Part 1: General requirements [9].
Of course, not all of the challenges and opportunities discussed above may apply to one specific device. Other, unmentioned ones may also arise with respect to it. Each one requires an individual approach. Selected cases are given below.
An example of a device manufactured using biotechnology is bacterial cellulose dressings used in the therapy of hard-to-heal wounds. Such dressings have many advantages, including that they provide gas exchange with the surroundings, and are durable and flexible. They can be produced in various shapes, adapted to needs. Moreover, they prevent secondary infections. In addition, such a dressing does not adhere to the skin, which makes it easier to change. It is also possible to saturate the dressing with various substances in order to accelerate healing. An insufficient production scale and high production cost, limited absorption capacity of the dressing, as well as, in the case of poor protection of the device, drying out during storage, constitute significant drawbacks of this technology [10].
Another example is synthetic collagen-based skin, which has found application in supporting the treatment of burns. Thus, the main advantages are the high purity of the collagen and its controlled quality, which translates into minimizing the risk of adverse effects. An additional advantage of collagen produced by this method is also the possibility of its modification, increasing stability and effectiveness in specific applications.
On the other hand, the disadvantages are the economic risk associated with production costs and the complicated technological process. A further risk may be the dependence of biocompatibility and functionality on the production method and the modifications applied [11].
Another of the devices manufactured using biotechnological methods – biopolymer bone implants – are used to support the regeneration of bone tissue and the stabilization of bone fragments. Undoubtedly, their advantage is their biodegradability, gradual absorption, and replacement by the patient's own bone tissue, which is associated with no need for a further operation. The disadvantages, on the other hand, may be: lower mechanical strength compared to, for example, titanium, the risk of an undesirable tissue reaction, e.g. inflammation, during absorption, as well as a shorter durability time than the time needed for the bone to heal [10].
The more innovative the device, the greater the risk, but also the greater the opportunity. Thus, for example, bioprinting makes it possible to faithfully reproduce tissue structures using bioinks and 3D printers. This is an intensively developed technology, which certainly carries with it numerous challenges, in which the cells must survive the printing process and then organize themselves into correct, functioning tissues, but which also offers proportionally greater possibilities. It is a way to solve the problems of donor shortages or the need for patients to use immunosuppression [12].
So what does the production of devices using biotechnology give companies? It provides an advantage in the form of innovation and competitiveness. This is a new sector, developing dynamically around the world, which offers great opportunities, development of knowledge, and real, measurable benefits for the economy. It develops medical technologies that are important for society.
In summary, the use of new technologies creates enormous opportunities for the manufacturer. However, it should be remembered that correct classification of the device and the choice of the appropriate conformity assessment procedure, as well as an efficiently functioning quality management system and the preparation of complete technical and clinical documentation in order to meet the requirements of the MDR, are the key to the efficient admission of medical devices to widespread use and to success on the market.
References:
[1] Fundamentals of pharmaceutical biotechnology. Kayser Oliver, Jagiellonian University Press, Kraków 2006.
[2] Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC.
[3] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU.
[4] MDCG 2019-14 Explanatory note on MDR codes. December 2019.
[5] Fundamentals of industrial biotechnology. Marek Adamczak et al., Wydawnictwo Naukowo-Techniczne, Warsaw 2012.
[6] European Pharmacopoeia (Ph. Eur.), 11th edition.
[7] Manual on borderline and classification for medical devices under Regulation (EU) 2017/745 on medical devices and Regulation (EU) 2017/746 on in vitro diagnostic medical devices. Version 5 – April 2026.
[8] MDCG 2021-24 Rev.1 Guidance on classification of medical devices. April 2026.
[9] wiedza.pkn.pl
[11] Collagen-Based Medical Devices for Regenerative Medicine and Tissue Engineering | Applied Biochemistry and Biotechnology. 2024, Appl Biochem Biotechnol.
[12] 3D bioprinting as the future of regenerative medicine and hope for transplantology. K. Gładysz et al. 2022, J Educ Health Sport.
Agnieszka Strabel is a biotechnologist and pharmaceutical technician whose professional interests focus on quality, quality control, and research and development in the life sciences sector.
She graduated in Biotechnology from the University of Silesia in Katowice and also obtained professional qualifications as a pharmaceutical technician. Her educational background combines knowledge of biotechnology, pharmacy, and laboratory work. During her studies, she participated in research projects related to, among other areas, vaccine biotechnology and the development of solutions with potential applications in healthcare.
She gained professional experience in the areas of quality management systems and quality control, as well as in research and development.
This background enables her to combine theoretical knowledge with a practical approach to laboratory and quality processes, as well as research and development activities.
Her professional interests include biotechnology, quality control, research and development, pharmaceutical technologies, and the development of innovative solutions for the life sciences sector.