|Year : 2022 | Volume
| Issue : 1 | Page : 6
Expert consensus on quality management system of bioprinting medical devices special requirements
Tao Li1, Dezhi Lu2, Ya Ren3, Tianchang Wang4, Yuanjing Xu5, Zhenjiang Ma4, Xin Sun4, Lei Qiang3, Xue Yang3, Guohong Shi5, Tao Xu6, Neng Xie7, Ming Guo8, Qingfeng Zeng9, Jian Sun10, Xiaodong Cao11, Bo Zhang12, Yong He13, Maling Gou14, Baolin Li15, Miao Zhou16, Weijie Peng17, Lei Hou18, Keqin Zhang19, Xin Jiang7, Xi Yang20, Chungkuang Chen21, Jinwu Wang4, Kerong Dai4
1 Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; Department of Orthopaedics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
2 School of Medicine, Shanghai University, Shanghai, China
3 School of Medicine, Southwest Jiaotong University College of Medicine, Chengdu, Sichuan Province, China
4 Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
5 School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
6 Department of Mechanical Engineering, Tsinghua University, Beijing, China
7 Shanghai Medical Device and Cosmetics Evaluation and Verification Center, Shanghai, China
8 Department of Thoracic and Cardiovascular Surgery, Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, China
9 International Center for Materials Discovery, School of Materials Science and Engineering, Northwestern Polytechnical University, Xi'an, Shaanxi Province, China
10 Department of Surgical, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, China
11 Material Science and Engineering School, South China University of Technology, Guangzhou, Guangdong Province, China
12 Department of Dermatology, Tangdu Hospital of Air Force Medical University, Xi'an, Shaanxi Province, China
13 State Key Laboratory of Fluid Power and Mechatronic Systems, School of Mechanical Engineering, Zhejiang University, Hangzhou, Zhejiang Province, China
14 Department of Biotherapy, Cancer Center, Sichuan University, Chengdu, Sichuan Province, China
15 Shenzhen Pingle Orthopedics Hospital, Shenzhen, Guangdong Province, China
16 Department of Stomatology, Guangdong Provincial People's Hospital, Guandong Academy of Medical Science, Guangzhou, Guangdong Province, China
17 Gannan Medical University, Guangzhou, Guangdong Province, China
18 Department of Cardiology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
19 College of Textile and Clothing Engineering, Soochow University, Suzhou, Jiangsu Province, China
20 Novaprint Therapeutics Suzhou Co., Ltd, Suzhou, Jiangsu Province, China
21 Tongguang (Kunshan) Biological Technology Co., Ltd., Shanghai, China
|Date of Submission||24-Oct-2021|
|Date of Decision||13-Nov-2021|
|Date of Acceptance||17-Nov-2021|
|Date of Web Publication||21-Apr-2022|
Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Room 701, No. 3 Building, 639 Zhizaoju Road, Shanghai 200011
Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Room 701, No. 3 Building, 639 Zhizaoju Road, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Bioprinting is expected to be a revolutionary technology for application in medicine, bringing hope to countless patients. For a long time, many patients have been experiencing a lack of suitable organs for transplantation, which eventually lead to loss of lives. Bioprinting technology can integrate cells, proteins, cytokines, and other supporting materials, such as biomaterials and hydrogels, to produce biomedical devices with biological functions. However, no bioprinting medical devices have been approved by the National Medical Products Administration, with specific registration and regulatory requirements for bioprinting medical devices still needing to be explored. To standardize the Bioprinting Medical Devices Special Requirements for Quality Management System, Chinese experts in relevant fields were organized to formulate this expert consensus.
Keywords: Bioprinting, Expert consensus, Medical devices, Quality management
|How to cite this article:|
Li T, Lu D, Ren Y, Wang T, Xu Y, Ma Z, Sun X, Qiang L, Yang X, Shi G, Xu T, Xie N, Guo M, Zeng Q, Sun J, Cao X, Zhang B, He Y, Gou M, Li B, Zhou M, Peng W, Hou L, Zhang K, Jiang X, Yang X, Chen C, Wang J, Dai K. Expert consensus on quality management system of bioprinting medical devices special requirements. Digit Med 2022;8:6
|How to cite this URL:|
Li T, Lu D, Ren Y, Wang T, Xu Y, Ma Z, Sun X, Qiang L, Yang X, Shi G, Xu T, Xie N, Guo M, Zeng Q, Sun J, Cao X, Zhang B, He Y, Gou M, Li B, Zhou M, Peng W, Hou L, Zhang K, Jiang X, Yang X, Chen C, Wang J, Dai K. Expert consensus on quality management system of bioprinting medical devices special requirements. Digit Med [serial online] 2022 [cited 2022 Dec 7];8:6. Available from: http://www.digitmedicine.com/text.asp?2022/8/1/6/343717
| Introduction|| |
Bioprinting is an additive manufacturing technology that allows the selective distribution of cells, biomaterials, growth factors, or combinations thereof to create living tissues and organs in three dimensions (3Ds).,, Bioprinting is poised to create a disruptive revolution in the medical field, bringing hope to countless patients. For a long time, many patients have experienced a lack of suitable organs for transplantation, which eventually lead to loss of lives.
In 2011, the U.S. Defense Advanced Research Projects Agency established a project to support the engineering and manufacturing of 3D human tissue structures, including the circulation, endocrine, gastrointestinal, immune, ectodermal, musculoskeletal, neurological, reproductive, respiratory, and urinary systems, 10 major physiological systems, through an in vitro platform and plan for their use in vivo. China provides great importance to the development of biological 3D printing technology and industry. The National Additive Manufacturing Industry Development Promotion Plan (2015–2016) considers additive manufacturing in the medical field as an important development direction. In the “13th Five-Year Plan,” National Major Science and Technology Special Projects launched by the Ministry of Science and Technology, biological 3D printing appeared in four special projects, including biomedical materials research and development, tissue and organ repair and replacement, stem cell and transformation research, as well as additive manufacturing and laser manufacturing.
It is also worth noting that there are currently no bioprinting-related standards in the world. Although China has proposed national standards in 3D printing, it has not yet established a complete 3D printing standard system covering design, materials, process equipment, product performance, certification, and testing, among others. The field of bioprinting is not able to bridge the technology and industry interface, as well as application promotion, thus slowing down the industrial development process. The lack of a standard system seriously restricts the application of bioprinting technology. Therefore, to promote the development of bioprinting, there is an urgent need for setting bioprinting medical device standards to solve the problem of bioprinting medical device registration and approval without relevant standards and norms to follow, as well as for guiding bioprinting medical devices enterprises to establish the corresponding production quality management system.
| Definition of Bioprinting Medical Devices|| |
Bioprinting technology can integrate cells, proteins, cytokines, and other supporting materials (such as biomaterials and hydrogels) to produce biomedical devices with biological functions. Bioprinting medical devices are manufactured by using additive manufacturing equipment and bioprinting technology, including but not limited to tissue engineering scaffolds and tissue-like organs, among others.
Bioprinting medical devices are often used as implants or body surface accessories. Bioprinting increases the tissue reconstruction function of existing implant devices by using cells or bioactive components collected from patients or by directly making new customized medical devices, such as bioprinting cartilages, skulls, ligaments, and other repair products, through bioprinting. At present, the sterilization methods and sample retention methods widely used for medical devices are usually not suitable for biomaterials, which pose a challenge to the supervision and registration regulations of medical devices.
Due to flexibility and particularity of bioprinting, the British Standards Institution proposes that bioprinting should first apply to the cells and other biological components, which are used as drugs in the clinic and subsequently combine these with other implanted devices. In the European Union (EU), drugs are regulated by the EU directive 2001/83/EC and EU directive 726/2004/EC. For advanced treatment methods involving genes, tissues, or cells, they should be regulated by the EU directive 726/2004/EC. If the main therapeutic effect of bioprinting devices on patients is exerted through drugs, such as active ingredients, it should be supervised as drugs; however, if the drug has only auxiliary effects, it should be classified as a combination of drugs and devices into Class III for registration and supervision.
In terms of feasibility, the EU guidance on the registration path of bioprinting devices is also applicable to China's medical device registration regulatory system. China has also issued relevant registration guidelines for pharmaceutical device combinations. However, no bioprinting medical devices have been approved by the National Medical Products Administration, with specific registration and regulatory requirements for bioprinting medical devices needing to be explored.
| Basic Process Elements of Design and Preparation of Bioprinting|| |
Condition examination and demand analysis
A clinician should conduct a professional clinical examination of the patient, including consultation and physical examination, and according to the actual situation, decide whether the patient needs B-ultrasound, radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) examination to assist in the diagnosis of the disease. The doctor should take a detailed history of the patient's illness. When necessary, a multidisciplinary discussion should be conducted to determine the patient's diagnosis. Finally, the specific content of bioprinted medical devices required by patients, such as tissue engineering scaffolds and organoids, is determined.
Developing bioprinting medical device plans
According to the basic situation of the patient and characteristics of clinical symptoms, including gender, age, clinical manifestations, and diagnosis, combined with the imaging examination results of the patient, including CT and MRI, among others, clinicians improve the preoperative diagnosis and surgical scheme design to prepare bioprinting medical devices for a specific purpose. The plan should be clear and reasonable, including needed parts, uses, materials, and other key points.
Acquisition of imaging data and reconstruction of target tissues
To make biological print stents, relevant data from patients need to be collected, such as their CT or (and) MRI imaging findings, especially for the reconstruction of the original group 3D model (generally for a STL format), creating a design according to the patient's original data and target group for print design support, ensuring that the support design would simulate the patient's anatomical features. The surface should be as porous or reticular as possible without affecting mechanical strength to ensure the growth of cells and formation of tissues.
Design and planning of print paths
The reconstructed 3D tissue model (generally in a STL format) is imported into the corresponding slice or path planning software, the organizational structure model (such as rotation and scaling) is set as required, and subsequently, the slice is set. The software should be able to set different voids and path shapes according to various requirements. Thereafter, the imported 3D model is transformed into a code (usually G-Code) that can be recognized by the printing system. After analyzing the printer software system, motion control is carried out. At the same time, temperature, air pressure control, nozzle switching, and other actions are performed according to the printer nozzle and different printing modes.
Acquisition and preparation of seed cells and bioinks
In 3D bioprinting, seed cells need to have specific or basic biological functions. The printed tissue can contain multiple cell types to allow stem cells to proliferate and differentiate into the desired cell types. From the clinical point of view, seed cells need to be obtained from the patient's body tissue to avoid a subsequent immune response; however, the limited life cycle and the difficulty of isolating and culminating the original cells limit the use of autologous seed cells. Stem cells derived from the bone marrow, fat, and amniotic fluid can proliferate and differentiate into specific cell types. In scientific research, seed cells are mostly bone marrow stem cells, chondrocytes, adipocytes, and embryonic stem cells, among others, which also are able to proliferate and induce differentiation.
Bioinks are prepared by seed cells and printing matrix materials, including natural hydrogels (sodium alginate, chitosan, silk protein, gelatin, collagen, and sodium hyaluronate), synthetic hydrogels (GelMA, Pluronic F127), and polycaprolactone, among others, as matrix materials as cell carriers can maintain the morphology of biological organs. They can also perform some functions, such as providing mechanical support.
Printing and manufacturing
Depending on the type of biological ink, the biological printing method can be inkjet bioprinting, laser bioprinting, or extrusion deposition printing, which would have corresponding printing equipment. Inkjet printing methods are of the piezoelectric and thermal bubble type. The advantage of this type of technology is that the print cell density and material viscosity can be controlled, but high temperature and high pressure can cause irreparable damage to cells and affect the activity of the tissue after printing. The advantage of this technology is its high resolution; however, the disadvantage is that it cannot print materials with a high viscosity. Extrusion deposition printing is common to the biological ink pipeline system with air pump pressurization so that the internal pressure of the pipeline is larger than the outside. Therefore, the internal biological ink flows out of the nozzle. In addition to the use of air pumps, piston or screw rods and other methods are also used, which can print highly viscous bioinks.
To load bioinks into the cylinder or tray of the printer in the printing process, a precise movement of the motion system should be controlled according to the designed path file and layer by layer, until the 3D entity of the target organization is gradually formed. Auxiliary systems, such as temperature control systems, forming chamber systems, and detection systems, among others, should cooperate with the motion system.
After the production of bioprinted medical devices is completed, appropriate posttreatment procedures should be carried out according to the actual situation of patients, mainly including washing off auxiliary reagents in the process of bioprinting. In vitro culture and induction differentiation should be carried out according to the actual situation.
Physical and chemical performance testing and biological function verification
For biological ink substrate materials, which are generally for microstructure characterization, compression performance, providing rheological properties, providing swelling properties, absorption performance, performance degradation in vivo and in vitro, and ion release performance, factors, such as testing, cytotoxicity support, cell proliferation, cell adhesion, migration, and the biological function of tissues and organs function, have to be validated. These include, for example, bioprinting 3D diastolic and systolic functions of heart valves, osteogenic properties of bone bioink, expression of cartilage-related markers of cartilage scaffolds, and detection of angiogenic performance of angiogenic scaffolds, among others.
Effect monitoring and feedback
The effect monitoring of bio-3D-printed scaffolds, tissues, and organs mainly focuses on the monitoring of their biological functions and immune responses of the body, such as bone formation of osteogenic scaffolds, angiogenesis promoted by angiogenic scaffolds, and the corresponding function monitoring of liver and kidney units. According to the feedback of functions, the design and preparation processes of bioprinting products are further optimized.
| Bioprinting Medical Device - Special Requirements for A Quality Management System|| |
Quality management system
Manufacturers engaged in bioprinting medical devices obtain the registration certificate and production license of relevant products, as well as carry out quality management and production activities in strict accordance with the Regulations on the Supervision and Administration of Medical Devices and Medical Device Production Quality Management Standards. If the bioprinted medical device is an aseptic medical device or implanted medical device, its quality management system should also meet the requirements of the corresponding implantable medical device appendix and/or aseptic medical device appendix in the Medical Device Production Quality Management Standards. If the bioprinting medical device is a personalized matching medical device or customized medical device, it should also meet the corresponding requirements of the Guidelines for Technical Review of Registration of Additive Manufacturing Medical Devices for Personalized Augmentation of Passive Implant Bone, Joint, and Oral Hard Tissue and regulations on supervision and administration of customized medical devices.
Institutions and personnel
The person in charge of production, technology, and quality of the bioprinting medical devices should have received professional training conducted by relevant authoritative physician training institutions or industry organizations or have corresponding professional knowledge of cell biology, microbiology, biochemistry, materials science, machinery, and computer science, as well as relevant experience in medical device research and development, production, and quality management. Relevant personnel should be able to correctly judge and manage practical problems in research and development, production, and/or quality management to ensure their ability to perform responsibilities of production and quality management.
Personnel exposed to bioprinting medical devices, including production, cleaning, and maintenance personnel, should regularly receive training in basic knowledge of hygiene and microbiology, cleaning operation, and biosafety protection according to their product risks and process characteristics. At the same time, relevant personnel should undergo a regular physical examination and present with established health files.
The design process of personalized matching or customized bioprinting medical devices should meet the relevant regulatory requirements. Medical personnel and engineering designers involved in product design and manufacturing should have a clear division of labor and responsibility boundaries and be able to communicate effectively. All staff involved in medical–industrial interaction should receive professional training conducted by relevant authoritative physician training institutions or industry organizations corresponding to their job requirements.
The key personnel should include at least the head of quality management and the person in charge of production. The person in charge of quality management should not be in charge of production at the same time.
The key personnel should work full time and possess professional knowledge related to their duties. At the same time, they should have relevant work experience appropriate to their positions or have received professional training carried out by relevant authoritative physician training institutions or industry organizations. They also should be able to meet the requirements of duties.
The technical and quality management directors engaged in the design and development of bioprinting medical devices should have more than 5 years of work experience in the design and development of medical devices or related work. They also should have received corresponding professional training carried out by relevant authoritative physician training institutions or industry organizations and should be able to perform their duties and requirements. Finally, they should be able to skillfully use YY/T 0316, which is the application of medical device risk management for product risk analysis and management.
Plants and facilities
The workshop on biological printing medical devices should comprehensively consider the factors of the ground, road, transportation, and surrounding biological environment to reduce the adverse impact of the environment on product quality and establish independent supporting facilities of biological printing medical devices and their special supporting equipment.
Separate functional rooms should be set for posttreatment processes (curing, culture, etc.).
Implantable or aseptic medical devices (including medical materials) that are required or processed by aseptic operation technology should be produced in a local Class 10,000 clean room (area) in an environment of not less than Class 100. They can also be produced at the same time; however, it is necessary to use different printing equipment to print various types or batches of products in different printing rooms with physical isolation, and appropriate management measures and file systems to prevent cross-contamination should be present.
The workshop producing bioprinting medical devices should fully consider the characteristics and product risks of cell biomaterials. According to the product technological process and production scale and as per the principle of reasonable design, layout, and use, the plant should be designed, and inspection sites, facilities, as well as a storage environment, should be present to ensure that the production and storage environment meet the product quality control requirements.
For the reception and sampling of exotic biological samples (including cells) and other collected materials, a special reception and sampling work area should be established to perform the functions of registration, numbering, initial inspection, verification, sampling, and temporary storage of collections.
The receiving and sampling work area should be isolated from the preparation area and have an independent clean environment. The sampling operation during receiving should be carried out in a clean environment of not less than Class 100. A special cell receiving room should be set up to check and sample the cells to be received, check the documents and records attached to the cells to be received, provide unique identification codes, as well as complete the receiving records and temporary storage and other operations.
The disposal of wastes generated in the production process of bioprinting medical devices should meet the relevant requirements of environmental protection and be specified in the quality management system documents. Protection against product pollution, especially biological pollution, should be documented, and the implementation of verification should be ensured.
The production equipment of bioprinting medical devices should be equipped with corresponding production and inspection equipment, as well as computer-aided design and production systems. It mainly includes biological printer equipment and necessary inspection and test equipment. Computer-aided design and production systems include design and printing software.
For software used in bioprinting, software name and version number should be specified. Software, such as computer-aided design and modeling systems, should ensure the correctness and integrity of data conversion. The biological printer can correctly read the data model and guide the biological printer to print according to the printing parameter information set by an operator to ensure the consistency and integrity of the final printing product structure, as well as the design structure. The influence of equipment on the composition and molecular structure of printing materials should be stable and controllable in the production process.
Purified water should be used in a clean environment of Grade 100,000 and above, and sterile injection water should be used in an environment of Grade 10,000 and above.
The quality management system documents of the bioprinting medical device manufacturer, including quality objectives, quality policies, quality manuals, procedure documents, technical documents, operation instructions, and records, should be integrated into the relevant contents of the bioprinting medical device. The technical documents of the bioprinting medical device should include the agreement signed between the enterprises and the medical institution, prescriptions issued by medical institutions, image data, patient information, and other medical–industrial interaction information, as well as the source, preservation, and use of cells and biomaterials. If regulations stipulate biological products related to bioprinting medical devices, relevant regulations should also be observed. The relevant records in the whole life cycle of bioprinted medical devices should be kept permanently to ensure the reproducibility of bioprinted medical devices.
For data information involving patient privacy, the enterprise should establish a database and bear the obligation of confidentiality. Under the premise of protecting patients' privacy, manufacturers can also achieve medical-industrial interaction and information exchange with medical institutions through the internet and other means for information on case situation, product design, and other information.
On the premise of obtaining the patient's informed consent, the acquisition, transmission, and storage of patient data should be implemented in a verified form to prevent the loss or damage of data, as well as ensure the correctness and integrity of data. Data should not be provided to other institutions or individuals except with the permission of patients and medical institutions.
When establishing the database, data management should be carried out in strict accordance with the relevant national laws and regulations to ensure that the patient data storage system is safe and effective, and the patient data information should not be stored on overseas servers. Various security measures can be taken to strictly protect data, including but not limited to the establishment of the intranet, private cloud, and private server.
Design and development
Design and planning
The design of bioprinting medical devices should be fully considered to meet the relevant requirements of Article 4.1, quality management system and regulations under the conditions of raw material characteristics, preparation processes, storage, transportation, and use. When planning the design and development of bioprinting medical devices, the various stages of product design and development should be clarified, and requirements, verification and conversion activities, personnel capabilities, division of labor and responsibility arrangement, as well as the traceability method of product design output corresponding to design input should be reviewed and confirmed to ensure that the products meet the requirements of intended use and regulations.
The design input of biological printing medical devices should determine the function, performance index availability, and safety requirements of the product, according to the intended use. When evaluating the suitability of regulatory requirements, the requirements of regulations and standards related to biomaterials and products should be fully considered; however, domestic and foreign information, as well as research literature on similar products, should be collected through multiple channels, with the risks of similar products to be fully evaluated. The risk above medical benefits should be clearly controlled, and a documented risk management report should be formed.
For example, when biologically printed medical devices are personalized matching or customized medical devices, the design link of the product should be extended to medical institutions as an important carrier of information input to the design. It should be able to fully and completely reflect the parameter characteristics of the personalized matching or customized medical devices to be designed.
At the time of purchase, the initial state of raw materials and processing aids, additives, and cross-linking agents should be clearly defined, including material or chemical information (general name, chemical name, commodity name, material supplier, etc.), material parameters, and material analysis certificates containing test methods. Testing methods for the chemical composition of their raw materials should also be established.
The enterprise should establish the quality control standard of raw materials, including the evaluation of the supplier, the acceptance standards and procedures of raw materials, and the consistency control of different batches of raw materials. Raw material suppliers should carry out procurement evaluation. Raw materials of different brands from different manufacturers, process parameters of bioprinting medical devices, and equipment from different manufacturers, as well as products made in combination with process parameters of final products, should be checked to ensure that they meet product technical requirements. Main raw materials that have not been verified should not be used for production, and main raw materials should be considered as qualified raw materials after verification and review.
When purchasing biological materials, such as cells, purchasing and acceptance activities should be carried out in strict accordance with the relevant laws and regulations, such as cell bank quality management self-discipline norms, stem cell preparation quality management self-discipline norms, and other relevant laws and regulations.
The management of biomaterials containing cells should comply with the requirements of Self-discipline Standard for Quality Management of Stem Cell Preparation and Self-discipline Standard for Quality Management of Cell Bank. Cell operations in an incomplete sealed state (such as isolation, culture, and filling), and nonterminal sterilization reagents and utensils in direct contact with cells should be carried out in a Class A environment under the background of Class B environment. The receiving and sampling work area of cells or biological samples/materials containing cells should be isolated from the preparation area and comprise an independent clean environment, and the sampling operation should be carried out in a Class A clean environment.
Verification and confirmation of equipment
Procedures that meet the requirements of the quality management system should be established to ensure that the production equipment of bioprinted medical devices should carry out installation confirmation, operation confirmation, and performance confirmation. The process parameters and software system of the augmented manufacturing system should be verified and confirmed. Depending on the characteristics of the product and process, the contents should be verified.
Computer software used in the production equipment of bioprinting medical devices should be checked before it is used for the first time and should be subsequently evaluated again after it is updated or the equipment is replaced. Specific methods and activities for the validation and revalidation of computer software should assess the associated risks. If computer software is used in the production process, it should meet the requirements of the YY/T 0287 Medical Device Quality Management System for Laws and Regulations.
Identification and traceability
The unique identification of bioprinted medical devices should be established, and the bioprinted medical devices should be identified by appropriate methods, with the identification of product status maintained in the whole process of production, storage, and use. The identification and traceability requirements of bioprinted medical devices should meet the requirements of quality management systems and regulations. To prevent confusion among products from different donors or different batches of products, the raw and auxiliary materials, as well as the production environment of biomaterials used in bioprinting medical devices, should be recorded. The production records of each batch of products include the product name, specification, model, raw material batch number, production batch number, unique identification, patient number, and other information. Medical worker should exchange the above-mentioned information while interacting. In addition to the above information, the production date, quantity, main equipment, process parameters, and operators, among others, should also be indicated on the instructions, packaging, and labels. The shipping note of all bioprinted medical devices should record the unique identification, quantity, specification, address, contact person, and contact information of dealers and users to ensure that they can be traced back to each production batch.
The design of the internal and external packaging of bioprinting medical devices should take into account the particularity of biomaterial products and protective control procedures, including isolation measures, to prevent exogenous pollution or cross-contamination that may be introduced in the production of raw materials and production operations. If the packaging cannot completely guarantee the protection of the product, it should be marked by labels and instructions. The product protection requirements should be documented during processing, storage, disposal, and circulation of the product, with the controlled process recorded.
Most bioprinting medical devices are of three types. Considering that they are exclusive customized devices, their whole-process supervision needs to be different from traditional medical device supervision. Although bioprinting has promoted the development of medical devices to a certain extent, its large-scale application still faces many challenges, especially at the regulatory level. First, research must be conducted and data must be extensively collected, including the opinions of experts, scholars, and doctors, as well as the information of patients to improve the personalized, rational, and systematic medical device supervision system. Medical practitioners are required to be important participants on the basis that the products fully meet the requirements of the product quality management system, and it can improve the standardization and binding force. Second, the mass production process of finished bioprinting medical devices should be approved by relevant government departments before they can be approved for listing, and they should be effectively supervised under relevant policies and regulations.
The enterprise should formulate release procedures and inspection methods according to the technical requirements of the products and should consider the following tests:
- The biological and chemical composition of product materials should meet relevant standards
- The physical and mechanical properties of the product should meet the relevant standards
- Consistency among product structures and input data models
- The performance index of the design output raw material
- Key processes of technical parameters
- Technical requirements of finished products
- The biological activity of the product should meet the design requirements
- Principles for formulating inspection rules.
Sales and after-sales service
The sales records of biologically printed medical device products should include the name, address, contact information, product name, specification, model, quantity, production batch number, period of validity, date of sale, medical device name, and registration number of the medical device. For customized medical devices, it should also include the name of the physician, patient information, and related records of the main raw materials, including stem cells.
If bioprinting medical devices contain active substances or have special needs for storage and transportation environment, such as low temperature and light avoidance, among others, these requirements should be made clear to dealers and medical institutions.
According to the particularity of biological printing medical devices, the presale, in-sale, and after-sale training and service of biological printing medical devices should be clearly defined in the product service control procedure of the quality management system.
Control of nonconforming products
Nonconforming products found before delivery should be marked, recorded, isolated, and reviewed, and the enterprise should be responsible for taking measures according to the results of the evaluation.
The nonconforming products found after delivery or use should be reviewed by the enterprise and clinical institutions, and appropriate remedial measures should be taken according to the results of the review to strengthen observations and increase the number of follow-ups.
When nonconforming products need to be destroyed, appropriate measures should be taken to deal with and control nonconforming products.
Adverse event monitoring, analysis, and improvement
Regulations for the analysis and study of the removed bioprinted medical devices should be formulated and documented. After obtaining them, the enterprise should analyze and study them to understand the information about the effectiveness and safety of the products to improve them.
A method for collecting information regarding adverse events related to medical devices, which correspond to the production products, should be established to timely collect information on the adverse events of medical devices.
Enterprises and medical institutions should jointly report the adverse events that occurred in the process of product use. Through the analysis and evaluation of adverse events, accumulating empirical data would improve the production quality system and process control of biological printing medical devices.
| Shortcoming and Prospects|| |
The maturity of 3D printing technology has promoted the generation and commercialization of the fourth-generation of intelligent medical devices, which has broad market prospects. With the promulgation of bioprinting medical device standards and expert consensus, a fast development of related industries is likely, and, at the same time, the development of the computer image processing technology, the bioprinting technology, and material science will further promote the development of bioprinting. The development in the field of medical equipment reduces manufacturing losses while ensuring safety and effectiveness, as well as ensures sophisticated and high-performance printing. However, the current development of bioprinting medical devices is still inadequate. The combination of the bioprinting technology and tissue engineering will finally be realized by printing and constructing artificial organs with high simulation, good tissue compatibility, and all physiological functions using human cells as raw materials, although there is still a long way to go.
Financial support and sponsorship
This study was supported by grants from National Key R&D Program of China (2018YFC2002300/2018YFC2001300); National Natural Science Foundation of China (81902195); Project of Shanghai Science and Technology Commission (18441903700/19XD1434200/19441908700/19441917500); Two-hundred Talent Support (20152224); Translational Medicine Innovation Project of Shanghai Jiao Tong University School of Medicine (TM201613/TM201915); Clinical Research Project of Multi-Disciplinary Team, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (201914).
Conflicts of interest
Kerong Dai is an Honorary Editors-in-Chief of the Journal. Jinwu Wang is an Associate Editor of the Journal. The article was subject to the Journal's standard procedures, with peer review handled independently of this editor and his research groups.
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