2020年6月23日，硅谷醫(yī)療3D打印創(chuàng)新平臺3DHEALS（3dheals.com）的“專家角/ Expert’s Corner”專欄發(fā)表了由3D科學(xué)谷聯(lián)合創(chuàng)始人朱琳撰寫的專欄文章' Progress in Commercialization of 3D Printed Orthopedic Implants in China Since 2019'。本期3D科學(xué)谷將分享發(fā)表在3DHEALS的原文及中文譯文。

▲3DHEALS Expert’s Corner

來源：3DHEALS

3DHEALS

Expert’s Corner

In our previous expert corner article published last year, ‘3D Printed Orthopedic Implants in China and the Challenges in Commercialization’, we reviewed the commercialization profiles of orthopedic 3D printing implants in China and showed that the Chinese orthopedic medical device manufacturing market has made slow progress towards commercialization compared to Europe and the United States.

However, since then, there was a clear acceleration of commercial transformation in China’s orthopedic 3D printing implant industry. In this article, we review the current commercialization progress of 3D printed implants in China involving: A) new 3D printed implant products; B) customized medical device supervision and management regulations; C) product registration technical review guidelines; D) group standards.

A. Newly listed 3D printing implant products

AK Medical

▲Figure 1: AK Medical 3D printed implants

Source: AK Medical

AK Medical is a pioneer in the research, development, manufacturing and commercial application of 3D printing metal implants in China. It is also a standardized orthopedic 3D printing metal implant manufacturer in the Asia-Pacific region.

In 2015-2016, AK Medical received three registration certificates from the China’s National Medical Products Administration (NMPA) for its 3D printed implants, including acetabular components, vertebral prostheses, and intervertebral fusion. In 2020, AK Medical received two more 3D printing implant products cleared by the NMPA. The newly cleared products are metal 3D printed pelvic defect matching prosthesis and metal 3D printed customized cervical fusion.

3D printing implants have become one of AK Medical’s core products. In 2019, the revenue of these products exceeded RMB 123 million, accounting for 13.3% of the total revenue.

JUST Medical

▲Figure 2:3D printed trabecular bone hip cup-standard

Source: JUST Medical

On July 12, 2019, Just Medical’s “trabecular bone hip prosthesis” was cleared by NMPA. JUST Medical has developed 3 types of 3D printed hip cups, namely trabecular bone hip cup-DDH, trabecular bone hip cup-standard, and trabecular bone hip cup-revision. All three models are manufactured through Electron Beam Melting (EBM) process.

B. Customized Medical Device Supervision and Management Regulations

On January 1, 2020, China’s “Regulations on the Supervision and Administration of Personalized Medical Devices (Trial)” was officially implemented. The interpretation of the regulations by NMPA includes four key points:

1. Customized implants are applicable, but patient-matched (or patient-specific) implants are not applicable. Personalized medical devices refer to medical devices designed and manufactured by medical device manufacturers according to the clinical needs of authorized medical personnel in medical institutions to meet the personalized requirements of patients. They are divided into customized medical devices and patient-matched medical devices.

2. Supervise by putting on record

Unlike standardized mass-produced medical devices, customized medical devices do not need to go through a long period of experimentation and approval process. However, there is requirement to implement pre-market documentation according to regulations.

Customized medical device manufacturing enterprises and medical institutions jointly act as documenting parties. Before producing and using customized medical devices, they should report to the drug regulatory department of the province, autonomous region, or municipality directly under the Central Government where the medical device manufacturing enterprise is located (the imported product is where the agent is located). From the perspective of risk control, customized medical devices cannot be entrusted to mass production, and the recording party should have the corresponding conditions.

3. Special requirements for design and processing involve personnel management, design and development, quality control, and traceability management.

4. When the use of a customized implant meets the pre-market approval requirements, such implants can be declared for registration.

According to the market observations of 3D Science Valley, after the formal implementation of the regulations by the NMPA, AK Medical and CHUNLI have submitted a number of applications for the record of the customized 3D printed implants.

▲Figure 3: Customized implants already recorded by AK Medical and CHUNLI

Source: 3D Science Valley ” White Paper of 3D Printing Orthopedic Implant 3.0″

As can be seen on the right side in Figure 3, the filing information needs to indicate the hospital and doctor who used the 3D printed implant, that is, this implant is limited to the doctor mentioned in the filing, and cannot be used for other purposes.

C. Guidelines for Technical Review of Product Registration

From the global perspective, the rapid commercialization progress was observed for 3D printed acetabular cups and spinal implants (especially fusion cages). The figure below shows the timeline of these 3D printed implants from its earliest commercialization in 2007 and onwards.

▲Figure 4: 3D printed hip cup commercialization progress

Source: 3D Science Valley ” White Paper of 3D Printing Orthopedic Implant 3.0″

The China NMPA is also promoting the commercial transformation of 3D printed hip cups, spinal fusion cages, and artificial vertebral implants. In 2019, it released a draft for consultation on the technical review guidelines for the above three types of standardized 3D printed implants.

D. Group standards

Promoted by the 3D Printing Medical Devices Committee of China Association for medical devices industry (3D CAMDI) the first five group standards for 3D printing medical devices in China were officially implemented on July 20, 2019 include:

1. Mechanical Equivalent Model of Customized Medical Device.

This standard specifies the methods for obtaining and analyzing mechanical equivalent models of customized medical devices. This standard applies to the mechanical analysis of some or all additive manufacturing products.

This standard specifies the requirements and precautions for the development of mechanical models to predict the loading of mechanical equivalent models in the evaluation of customized medical device mechanical equivalent models. The methods in this standard can be used to evaluate the equivalent mechanical models of a series of customized medical devices to meet the requirements of the devices. The procedures for model verification and validation are recommended in this standard to help determine whether the analysis of the mechanical equivalent model complies with the recommended guidelines. This standard recommends what should be included in the analysis report.

2. Special Requirements for Quality Control System of Customized Medical Devices

Customized medical devices have an important role in promoting the development of personalized medicine. However, due to the individuality of the design and production of such products, it is difficult for conventional testing and evaluation methods to ensure the safety and effectiveness of such products. Therefore, the quality control process of such products, especially high-risk customized medical devices, are particularly important. This standard specifies the special requirements for customized medical device quality control systems.

This standard applies to customized medical devices, which include additive manufactured implantable and non-implantable medical devices. This standard is a special requirement for the quality management specification of the entire manufacturing processes of customized medical devices.

These system requirements and process control minimize the risk, guarantee traceability of products, unify the mode of medical and industrial interactions, and strengthen the verification and confirmation of the design. The processing technology parameters should be met to ensure product quality.

Customized medical device design and production enterprises need medical device registration certificates and medical device production licenses, and cannot expand activities to other medical device registration certificate holders, and are not allowed to outsource production.

3. Matched Artificial Temporom and ibular Joint

This standard specifies the product design and type, material, design evaluation, test method, quality control, manufacturing, sterilization, packaging, and information provided by the manufacturer of matched artificial temporomandibular joints.

This standard is applicable to matching artificial temporomandibular joints. This product is suitable for the repair or reconstruction of temporomandibular joints and adjacent bone tissues in oral and maxillofacial surgery, head, neck, and nose surgery.

4. Internet of customized Additive Manufacturing medical devices and general requirements for realization conditions

This standard specifies the terms and definitions for the implementation process of customized additive manufacturing (3D printing) medical device products, related parties, related responsibilities, Internet information platform implementation conditions, development and maintenance, and security requirements under the Internet conditions.

5. Monitoring and judging indicators and receiving conditions of the interactive process of Customized medical devices for Doctor and Engineer.

This standard applies to customized medical devices such as bones, joints, and oral hard tissue. Clarify the process and method of customized medical device quality assurance, standardize the relevant behaviors of medical-industrial interaction of customized medical devices, and realize the sharing and communication of medical-industrial information, monitoring and data acquisition, design and development, and devices from clinical needs to production to clinical use. The whole process of production, delivery, acceptance and follow-up.

Conclusion:

The lack of relevant regulations and standards is the main challenge restricting the industrial application of 3D printed medical devices in China. Since 2019, in addition to the newly-listed products, China has made breakthrough progress in 3D printing implant-related technical review guidelines, management regulations and group standards. The establishment and improvement of laws and standards will promote China’s 3D printed orthopedic implants to enter the road of accelerated industrialization.

在2019年“3DHEALS Expert’s Corner”專欄文章《3D打印骨科植入物在中國的應(yīng)用概況以及商業(yè)轉(zhuǎn)化中的挑戰(zhàn)》中,我們回顧了2019年之前，中國的骨科3D打印植入物商業(yè)轉(zhuǎn)化概況。相比歐美市場，中國骨科醫(yī)療器械制造商在3D打印骨科植入物商業(yè)轉(zhuǎn)化方面的進(jìn)展較慢。

不過，2019年以來，中國骨科3D打印植入物的商業(yè)轉(zhuǎn)化出現(xiàn)了明顯的加速跑趨勢。在本期專欄中，我們將從中國2019年以來新增上市3D打印植入物產(chǎn)品、定制式醫(yī)療器械監(jiān)督管理規(guī)定、產(chǎn)品注冊技術(shù)審查指導(dǎo)原則、團(tuán)體標(biāo)準(zhǔn)四個角度，回顧2019年至今，中國骨科3D打印植入物的商業(yè)化進(jìn)展。

l 新增上市3D打印產(chǎn)品

愛康醫(yī)療

愛康醫(yī)療是中國3D打印金屬植入物研發(fā)、制造與商業(yè)應(yīng)用等方面的開拓者，同時也是亞太地區(qū)規(guī)范化的骨科3D打印金屬植入物制造商。

2015-2016年，北京愛康宜誠醫(yī)療器材股份有限公司從國家藥品監(jiān)督管理局獲得了三個3D打印植入物注冊證：髖臼部件和椎體假體、椎間融合器。2020年，愛康新增兩款獲得國家醫(yī)療器械監(jiān)督局Ⅲ類器械注冊證的3D打印植入物產(chǎn)品，分別是：金屬3D打印骨盆缺損匹配假體與金屬3D打印定制化頸椎融合體。

3D打印植入物已成為愛康醫(yī)療的核心產(chǎn)品之一。2019年3D打印產(chǎn)品營收超過1.23億元，占總收入的13.3%。

嘉思特醫(yī)療

2019年7月12日，嘉思特的骨小梁髖關(guān)節(jié)假體產(chǎn)品獲得國家醫(yī)療器械監(jiān)督局Ⅲ類器械注冊證。嘉思特開發(fā)了3種型號的3D打印髖臼杯：骨小梁髖臼-DDH與骨小梁髖臼-標(biāo)準(zhǔn)型與骨小梁髖臼-翻修。3種型號均采用電子束熔融3D打印技術(shù)制造。

l 定制式醫(yī)療器械監(jiān)督管理規(guī)定

2020年1月1日中國《定制式醫(yī)療器械監(jiān)督管理規(guī)定（試行）》正式實施。中國國家藥品監(jiān)督管理局對該規(guī)定的解讀，包括四個關(guān)鍵要點：

1. 定制式植入物使用，而患者匹配型不適用；

個性化醫(yī)療器械是指醫(yī)療器械生產(chǎn)企業(yè)根據(jù)醫(yī)療機(jī)構(gòu)經(jīng)授權(quán)的醫(yī)務(wù)人員提出的臨床需求設(shè)計和制造的、滿足患者個性化要求的醫(yī)療器械，分為定制式醫(yī)療器械和患者匹配醫(yī)療器械。

2. 采用備案的方式進(jìn)行監(jiān)管；

與標(biāo)準(zhǔn)化批量生產(chǎn)的醫(yī)療器械不同，定制式醫(yī)療器械無需經(jīng)過漫長的實驗與審批管理周期，而是按規(guī)定實行上市前備案管理。

定制式醫(yī)療器械生產(chǎn)企業(yè)與醫(yī)療機(jī)構(gòu)共同作為備案人，在生產(chǎn)、使用定制式醫(yī)療器械前應(yīng)當(dāng)向醫(yī)療器械生產(chǎn)企業(yè)所在地（進(jìn)口產(chǎn)品為代理人所在地）省、自治區(qū)、直轄市藥品監(jiān)督管理部門備案。從風(fēng)險控制的角度出發(fā)，定制式醫(yī)療器械不得委托生產(chǎn)，備案人應(yīng)當(dāng)具備相應(yīng)條件。

3. 設(shè)計加工特殊要求涉及人員、設(shè)計開發(fā)、質(zhì)量控制、追溯管理。

4. 當(dāng)一種定制式植入物的使用數(shù)量達(dá)到上市前審批要求之后，可對此類植入物注冊。

根據(jù)3D科學(xué)谷的市場觀察，在該規(guī)定正式實施后，愛康醫(yī)療與春立正達(dá)開展了多個定制式植入物的備案申請。

▲圖：愛康與春立正達(dá)已備案的定制式植入物

來源：《3D打印與骨科植入物白皮書3.0》（七月發(fā)布）

從上圖中的右圖可以看到，備案信息中需要注明使用植入物的醫(yī)院、醫(yī)生，也就是這款植入物僅限于備案中提及的醫(yī)生使用，而不能在其他用途中使用。

l 產(chǎn)品注冊技術(shù)審查指導(dǎo)原則

從全球骨科3D打印植入物商業(yè)轉(zhuǎn)化情況來看，進(jìn)展最快的是3D打印髖臼杯與脊柱植入物（尤其是融合器）。下圖顯示了全球范圍內(nèi)典型的3D打印髖臼杯產(chǎn)品，3D打印髖臼杯的商業(yè)化最早在2007年就開始了。

▲圖：3D打印髖臼杯商業(yè)化進(jìn)展

來源：《3D打印與骨科植入物白皮書3.0》（七月發(fā)布）

中國國家醫(yī)療器械監(jiān)督管理局也在推動髖臼杯、脊柱融合器與人工椎體3D打印植入物的商業(yè)轉(zhuǎn)化。2019年，他們發(fā)布了以上三類標(biāo)準(zhǔn)化3D打印植入物的技術(shù)審查指導(dǎo)原則征求意見稿。

l 團(tuán)體標(biāo)準(zhǔn)

在3D打印醫(yī)療器械專業(yè)委員會的推動下，中國3D打印醫(yī)療器械第一批五項團(tuán)體標(biāo)準(zhǔn)在2019年7月20日正式實施。

第一批五項團(tuán)體標(biāo)準(zhǔn)包括：《定制式醫(yī)療器械力學(xué)等效模型》、《定制式醫(yī)療器械質(zhì)量體系特殊要求》、《匹配式人工顳下頜關(guān)節(jié)》、《定制式增材制造醫(yī)療器械的互聯(lián)網(wǎng)實現(xiàn)條件的通用要求》、《定制式醫(yī)療器械醫(yī)工交互全過程監(jiān)控及判定指標(biāo)與接收條件》。 

l 總結(jié)

相關(guān)法規(guī)和標(biāo)準(zhǔn)的缺失，是制約3D打印醫(yī)療器械在中國產(chǎn)業(yè)化應(yīng)用的主要挑戰(zhàn)。2019年以來，除了新增的上市產(chǎn)品，中國在3D打印植入物相關(guān)技術(shù)審查指導(dǎo)原則、管理規(guī)定以及團(tuán)體標(biāo)準(zhǔn)方面取得了突破性的進(jìn)展。法規(guī)與標(biāo)準(zhǔn)的建立、完善，將推動中國3D打印骨科植入物進(jìn)入產(chǎn)業(yè)化加速跑之路。

本文轉(zhuǎn)自3D科學(xué)谷