3D列印醫療器材上市前的法規要求

李子偉工業技術研究院量測技術發展中心

106 年12 月 19 日

1

Content

1. 3D printing/Additive Manufacturing

2. Current medical applications

3. Regulatory considerations

4. Standardization/Measurement

2

1. 3D Printing/Additive Manufacturing (AM)

3資料來源：維基百科，國立科學工藝博物館，臺大視覺素養學習網，US FDA

1045年 畢昇(約970年—1051年)活字印刷術

1984年 Charles W. Hull(1939~) Stereolithography(SLA)

• 機械加工：車、銑、鑽、磨、鋸、放電、冲、壓、焊、熱處理、表面處理；水刀、雷射、超音波、化學蝕刻。

• 塑膠成型：.射出、熱、抽出、壓縮、吹塑、發泡、迴轉、注模、瀝鑄。

• 材料接合加工

Bioprinting: The use of 3D printing technology with materials that incorporate viable living cells, e.g. to produce tissue for reconstructive surgery

……Oxford Dictionary

Additive Manufacturing

ASTM F 2792-1

• Additive manufacturing is the process of joining materials to make objects from 3D model data, usually layer upon layer, as opposed to subtractive manufacturing methodologies, such as traditional machining

ISO/ASTM 52900:2015-12 (E) Additive manufacturing - General principles – Terminology

• 2.1.2 additive manufacturing AM

process of joining materials to make parts (2.6.1) from 3D model data, usually layer (2.3.10) upon layer, as opposed to subtractive manufacturing and formative manufacturing methodologies

Note 1 to entry: Historical terms: additive fabrication, additive processes, additive techniques, additive layer manufacturing, layer manufacturing, solid freeform fabrication and freeform fabrication.

Note 2 to entry: The meaning of “additive-”, “subtractive-” and “formative-” manufacturing methodologies are further discussed in Annex A.

4資料來源: EPMA, Introduction to Additive Manufacturing Technology

Cumulative AM machines installed, 1988~2011

資料來源：Additive Manufacturing: Potential Implications for US Manufacturing Competitiveness, to Journal of International Commerce and Economics, USITC, Sep. 2014

Main Process Steps

5資料來源: EPMA, Introduction to Additive Manufacturing Technology (provided by Fraunhofer)

3D Printing/AM Processes Categoriesby ASTM F42

6資料來源：US DOE, Additive Manufacturing Technology Assessment

Process Brief Description Related Technologies Companies Materials

Powder Bed Fusion

Thermal energy selectively fuses regions of a powder bed

Electron beam melting (EBM), selective laser sintering (SLS), selective heat sintering (SHS), and direct metal laser sintering (DMLS)

EOS (Germany), 3D System (US), Arcam(Sweden)

Metals, Polymers

DirectedEnergy Deposition

Focused thermal energy isused to fuse materials by melting as the material is being deposited

Laser metal deposition (LMD) Optomec (US), POM (US) Metals

Material Extrusion

Material is selectivelydispensed through a nozzle or orifice

Fused deposition modeling (FDM)

Stratasys (Israel), Bits from Bytes (UK)

Polymers

Vat photopolymerization

Liquid photopolymer in a vat is selectively cured by light-activated polymerization

Stereolithography (SLA), digital light processing (DLP)

3D Systems (US), Envisiontec (Germany)

Photopolymers

Binder Jetting

A liquid bonding agent is selectively deposited to joinpowder materials

Powder bed and inkjet head (PBIH), plaster-based 3D printing (PP)

3D Systems (US), ExOne(US)

Polymers, Foundry Sans Materials

MaterialJetting

Droplets of build material are selectively deposited

Multi-jet modeling (MJM)Objet (Israel), 3D System (US)

Polymers, Waxes

Sheet Lamination

Sheets of materials are bonded from an object

Laminated object manufacturing (LOM), ultrasonic consolidation (UC)

Fabrisonic (US), Mcor(Ireland)

Papers, Metals

3D Printing/AM Processes

7資料來源：US DOE, Additive Manufacturing Technology Assessment

State of starting material

ProcessMaterial preparation

Layer creation technique

Phase change

Typical material

Application

Liquid SLALiquid resin in a vat

Laser scanning/light projection

Photopoly-merization

UV curable resin ceramic suspension

Prototypes, casting patterns, soft tooling

MJMLiquid polymerin jet

Ink-jet printingCooling & photopoly-merization

UV curableacrylic plastic, wax

Prototypes, casting patterns

RFPLiquid droplet in nozzle

On-demand droplet deposition

Solidificationby freezing

WaterPrototypes, casting pattern

Filament/Paste

FDMFilament meltedin nozzle

Continuous extrusion and deposition

Solidification by cooling

Thermoplastics, waxes

Prototypes, casting patterns

Robocasting Paste in nozzleContinuous extrusion

-Ceramic paste

Functional parts

FEF Paste in nozzleContinuous extrusion

Solidification by freezing

Ceramic paste

Functional parts

3D Printing/AM Processes

8資料來源：US DOE, Additive Manufacturing Technology Assessment

State of starting material

ProcessMaterial preparation

Layer creation technique

Phase change

Typical material

Application

Powder SLS Powder in bed Laser scanningPartial melting

Thermoplastics, waxes, metal powder, ceramic powder

Prototypes, casting patterns, metal and ceramic performs (to be sintered and infiltrated)

SLM Powder in bed Laser scanning Full meting metalTooling, functional parts

EBM Powder in bedElectron beam scanning

Full melting metalTooling, functional parts

LMDPowder injectionthrough nozzle

On-demand powder injection and melted by laser

Full melting metalTooling, metal part repair, functional parts

3DPPowder in bed Drop-on-demand binder printing

Drop-on-demand binder printing

-

Polymer, Metal, Ceramic, other powders

Prototypes, casting shells, tooling

Solid sheet

LOM Laser cutting

Feeding and binding of sheets with adhesives

-Paper, plastic, metal

Prototypes,casting models

2. Current Medical Applications

• Anatomical models for surgical preparation

• Bioprinting cells, tissues and organs• Technologies: laser-based, inkjet-based, extrusion-based

• Pre-clinical testing during drug discovery or cosmetic product development

• Tissue grafts/ implants

• Customized implants and prostheses• Patient Specific Implants: dental (implant, abutment, crown, bridges, teeth,

coping), orthopedics (hearing aids, cranial, hip, knee, spine…)

• Patient Specific Disposable Instruments, endoscope, surgical instruments

• Patient Specific Prostheses and Orthoses

• Custom 3D-printed dosages forms and drug delivery devices• Personalized drug dosing

• Unique dosage forms

• Complex drug-release profiles

資料來源：C. Lee Ventola, Medical Applications for 3d Printing, 2014Additive Manufacturing in the Medical Field, EOS, 2013 9

10

Gartner Hype Cycle for 3D Printing 2017

3. Regulatory Considerations

11

106.06.14 藥事法

105.09.28 藥事法施行細則

104.08.05 藥物回收處理辦法

93.08.31 嚴重藥物不良反應通報辦法

102.11.21 藥物安全監視管理辦法

102.08.02 藥物委託製造及檢驗作業準則

102.07.04 藥物製造工廠設廠標準

102.07.30 藥物優良製造準則

103.02.21 藥物製造業者檢查辦法

102.08.08 藥物製造許可及優良製造證明

文件核發辦法

104.06.03 醫療器材管理辦法

92.04.30 藥物樣品贈品管理辦法

106.03.30 醫療器材查驗登記審查準則

104.05.13 西藥及醫療器材查驗登記審查

費收費標準

憲法

法律

行政命令(法

規命令與行

政規則)

規程、規則、

細則、辦法、

綱要、標準、

準則

依據：中央法規標準法、行政程序法

醫療器材採認標準104.09.18 918項

醫療器材臨床前測試基準、體外診斷醫療器材技術基準與查驗登記審查指引 61份

體外診斷醫療器材查驗登記須知(106.03.15)

家用體外診斷醫療器材查驗登記須知(102.7.17)

醫療器材安全性與功效性基本規範及技術文件摘要指引」(101.12.03)

藥物非臨床試驗優良實驗室操作規範(GLP)

醫療器材優良臨床作業規範(GCP, 104.10.16)

醫療器材優良安全監視規範(GVP, 100.10.14)

醫療器材定義

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• 醫療器材：本法所稱醫療器材，係用於診斷、治療、減輕、直接預防人類疾

病、調節生育，或足以影響人類身體結構及機能，且非以藥理、免疫或代謝

方法作用於人體，以達成其主要功能之儀器、器械、用具、物質、軟體、體

外試劑及其相關物品。

前項醫療器材，中央衛生主管機關應視實際需要，就其範圍、種類、管理及其

他應管理事項，訂定醫療器材管理辦法規範之。「 (藥事法第十三條102-05-

08修正)

• 體外診斷醫療器材（In Vitro Diagnostic Device, IVD）：「係指蒐集、準備

及檢查取自於人體之檢體，作為診斷疾病或其他狀況（含健康狀態之決定）

而使用之診斷試劑、儀器或系統等醫療器材。」(醫療器材查驗登記準則第九

條)

• 新醫療器材*：無類似品經衛生福利部核准者

*醫療法施行細則第二條「所稱新醫療器材，指以新原理、新結構、新材料或新材料組合所製造，其醫療之安全性

或效能尚未經醫學證實之醫療器材。」

西藥及醫療器材查驗登記審查費收費標準第二條「新原理、新結構、新材料、新效能或無類似品者之醫療器材。」

體外診斷試劑查驗登記須知第二條第七項「無同類產品可供比對測試及新檢驗項目、新方法、新原理之體外診斷醫

療器材，則以新體外診斷醫療器材管理」

醫療器材上市前管理

醫療器材 分類(專科別) 次分類(用途別)

體外診斷醫療器材In Vitro Diagnostic Medical Device

共計509品項

(1)臨床化學及臨床毒理學227品項

臨床化學試驗系統，臨床實驗室儀器，臨床毒理學試驗系統

(2)血液學及病理學 100品項

生物染色，細胞組織培養產品，病理學儀器與附件，檢體準備試劑，自動化與半自動化血液器材，手動血液器材，血液學套組，血液學試劑，用於血液與血液產品製造業者之產品，用於人類細胞組織與相關產品之(HCT/Ps)製造業者之產品

(3)免疫學及微生物學182品項

診斷器材，微生物學器材，血清學試劑，免疫學實驗室儀器與試劑，免疫學試驗系統，腫瘤相關抗原免疫試驗系統，微生物學器材

醫療器材

Medical Device

共1,207品項

(4)麻醉學 (5)心臟血管醫學(6)牙科學 (7)耳鼻喉科學 (8)胃腸病科學及泌尿科學 (9)一般及整形外科手術 (10)一般醫院及個人使用裝置 (11)神經科學 (12)婦產科學 (13)眼科學 (14)骨科學 (15)物理醫學科學 (16)放射學科學

診斷器材，監控器材，治療器材，雜項器材，彌補器材，手術器材，生殖輔助器材

• 醫療器材屬性管理查詢申請• 複合性藥物判定要點

13

1. 製造業藥商許可執照/販賣業藥商許可執照(地方衛生機關)

• 醫療器材販賣業者須取得藥商許可執照方得以輸入、販賣醫療器材

• 國產醫療器材製造業者須取得工廠登記證、製造業藥商許可證、依規定申請醫療

器材優良製造規範查核方得以製造、販賣(所生產之)醫療器材

• 工廠登記證與製造業藥商許可證由縣市地方政府實地檢查後發給

2. 標示與廣告(地方衛生機關)

– 藥事法第七章第66~70條

– 藥事法第八章第75條：仿單標籤

3. 醫療器材許可證(中央衛生機關)

– 醫療器材管理辦法

– 醫療器材查驗登記審查準則

– 藥物製造工廠檢查辦法

– 藥物製造工廠設廠標準

– 藥物優良製造準則─醫療器材優良製造規範

醫療器材上市前管理

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醫療器材分級、查驗登記與GMP

等級 一 二 三

分類品項之數量(列屬醫療器材管理辦法附件一共1712項)

737

IVD 290(A類137, B類40, C類113)

943

IVD 225(A類92, B類64, C類69)

152

IVD 11(A類2, B類4, C類5)

國產GMP/輸入QSD

精要模式

(列屬醫療器材管理辦法附件二且未滅菌或不具量

測功能者)

標準模式 標準模式

查驗登記 臨櫃辦理

技術資料

除適用簡化規定者外，無類似品醫療器材，須提供臨床試驗資料。

(IVD臨床評估資料)

技術資料

臨床試驗資料

(IVD臨床評估資料)

資料來源：93.12醫療器材管理辦法附件一以及95.06.06, 99.4.27, 99.6.18, 99.8.10, 101.7.27, 103.1.5, 103.9.22, 104.6.3修正，本表統計資料僅供參考，以食品藥物管理局最新公告為準

15

醫療器材上市流程

製造業藥商/販賣業藥商

醫療器材分類分級

第一等級

無類似品之醫療器材技術審查

技術審查臨櫃辦理

醫療器材許可證

醫療器材優良製造規範認可登錄

第二/三等級以及無類似品之醫療器材

設計開發、臨床前評估、臨床評估、彙整技術資料

無菌或具量測功能

16

• 積層製造（3D 列印）醫療器材管理指引草案，衛福部食藥署，106-11-8/106-12-15

• AHWP/WG1/P001:2017 Handbook for Approval of Patient-matched Medical Devices Using 3D Printers, December 8, 2017

• 中國國家藥監總局《需進行臨床試驗審批的第三類醫療器械目錄》8.定製增材製造（3D列印）骨科植入物。

• Proposed regulatory changes related to personalised and 3D printed medical devices, Consultation paper, Version 1.0, , Therapeutic Goods Administration, Australia, November 2017

• Technical Considerations for Additive Manufactured Medical Devices, US FDA, December 5, 2017

Regulatory Document

17

18

Regulatory Compliance

Patient needs

Datatransfer, design, modify

Std. HF database

Design V /V & transfer

3D printing/AM equipment

3D Printing/AM

test tools

3D Printing/AM

MD Production

3D printing/AM

Finished Prouct

Patient data/image

capture

3D printing/AM

MD Processor

3D printing/AM

Materials

3D printing/AM Modelling tools

Implantation

國際趨勢

US FDA EU (UKMHRA)

Japan Korea MFDA

PRC CFDA

Australia TGA

AHWP

法規/規範

Technicalconsiderations for Additive Manufactured Medical Devices (Dec 2017)

Custom-made devices (2013)

1.以患者影像數據作為客製化3D列印骨科植入物依據之評價指標2.3D列印技術用於骨科植入物之評價指標3. 運用3D列印技術的齒科補綴裝置開發導引手冊2017(指南)4. 顏面頭蓋骨所適用的3D列印陶瓷製定製補骨材料相關評價指標

1. 以3D列印機配合患者訂製植牙固定體之准許審核指導方針

2. 使用3D列印機所製造的病患客製化骨科矯正型植入物許可審查指南手冊

未來將擬訂”定制式醫療器械管理規定”

TGA公開徵求意見” Proposed regulatory changes related to personalized and 3D printed medical devices”

Handbook for Approval of Patient-matched Medical Devices Using 3D Printers

列印機

不以醫療器材管理

軟體

因應功能是否符合醫療器材定義，而相應管理

Technical Considerations

20

User needs

CAD to CAMMaterials

Post-market surveillance

Final customized products produced by Laser Sintering

Printing Characteristics and Parameters

Design, Printing, and Post Printing Validation

Safety and Function Assessment

資料來源：K. Vorvolakos, et al., US FDA, Additive Manufacturing and Medical Devices, 2015

• Approves SPRITAM drug for the treatment of epilepsy by using 3D printing technology

• Approves 85 3D Medical Devices through 510(k) or Emergency Use

• Oct 2014 Workshop

• No new regulation

• Guidance 2017

US FDA Activities on 3D Printing

21

22

資料來源：Process of 3D Printing Medical Devices, US FDA

Printing

Process Validation and Verification

• Device Design: A design is created and validated using digital models with pre-specified sizes or digital models matched to a patient’s anatomy.

• Software Workflow: The digital device design is converted to a buildable file that is sent to the printer. This file will often divide the design into layers, include additional support material to aid printing, and tell the printer where to build the device on the printer platform to prepare it for printing. The 3D printer often also requires some preparation to build different designs by changing settings for the material, type of design, and intended use.

• Material Controls: Like any manufacturing process, 3D printing needs high quality materials that meet consistent specifications to build consistent high quality devices. To ensure this, procedures, requirements, and agreements called material controls, which must be checked for every batch of material, are established between the suppliers, purchasers, and end-users of the material.

23

資料來源：Process of 3D Printing Medical Devices, US FDA

Design and Manufacturing Process Considerations

• Printing: The object is printed using the design specifications included in the file.

• Post-Processing: After printing is complete, one or more post-processing steps may be performed on the device or component. These may include cleaning to remove residual debris, controlled cooling (also called annealing), and/or additional steps such as drilling, cutting, polishing, and sterilization.

• Process Validation and Verification: Some device or component characteristics can be checked individually after they are produced to make sure they will function properly and meet specifications. This is especially true of geometric features which can be checked quickly and nondestructively. When other functional features, such as mechanical strength, cannot be checked individually because the test could destroy the object or is impractical, manufacturers validate their processes prior to production. Process validation ensures that a manufacturing process will produce product that is within defined specifications, as long as specified processing parameters are monitored and controlled.

24

資料來源：Process of 3D Printing Medical Devices, US FDA

Design and Manufacturing Process Considerations

• Testing: Device testing methods and results are submitted to the FDA to show that the device meets regulatory requirements and is reasonably safe and effective for its intended use. Each device or type of device has its own set of tests that may be based on FDA Guidance documents, international standards, or internal process controls. Devices manufactured by 3D printing are generally subject to the same regulatory requirements as more traditionally manufactured medical devices.

• The FDA typically clears or approves finished medical devices, not specific materials for general use in the manufacture of medical devices, including materials that may be used in the manufacture of 3D printed devices.

• For dental devices, including those manufactured using 3D printing technology, the FDA clears some engineered materials for a specific intended use as a device. These specific materials are considered finished devices that are suitable for use by health care professionals and are patient-matched or fitted at the point of care.

25

資料來源：Process of 3D Printing Medical Devices, US FDA

Design and Manufacturing Process Considerations

1. Design and Manufacturing Process Considerations

A. Overall Device Design

B. Patient-Matched Device Design

C. Software Workflow

1) File Format Conversions

2) Digital Device Design to Physical Device

3) Validation and Automating Software Processes

D. Material Controls

1) Starting Material

2) Material Reuse

E. Post-Processing

F. Process Validation and Acceptance Activities

1) Process Validation

2) Revalidation

3) Acceptance Activities

4) Test Coupons

G. Quality Data

26

Technical Considerations for Additive Manufactured Medical Devices, US FDA, December 5, 2017

資料來源：Technical Considerations for Additive Manufactured Medical Devices, US FDA, December 5, 2017

2. Device Testing Consideration

A. Device Description

B. Mechanical Testing

C. Dimensional Measurements

D. Material Characterization

1) Material Chemistry

2) Material Physical Properties

E. Removing Manufacturing Material Residues and

Sterilization

F. Biocompatibility

3. Labeling

27

Technical Considerations for Additive Manufactured Medical Devices, US FDA, December 5, 2017

資料來源：Technical Considerations for Additive Manufactured Medical Devices, US FDA, December 5, 2017

積層製造（3D 列印）醫療器材

管理指引草案106-12-15

前言

背景說明

名詞定義

適用範圍

客製化醫材

3D列印技術相關醫材屬性管理原則

3D列印軟體工作流程管控

品質與製造管控

成品測試

28

分類

列屬醫療器材 不以醫療器材管理

機台

電腦輔助設計與製造(CAD/CAM)之光學取模系統機台

僅執行3D列印製造功能之機台

軟體

手術規劃軟體(如協助規劃特定手術類型、模擬手術過程、設計三維數位手術模型或手術導板等之軟體)

教學用軟體 製程軟體 設計操作軟體

材料

效能宣稱符合醫療器材定義之最終成品，列屬醫療器材，對於未宣稱特定醫療用途之原始材料、列印材料或製造過程中使用之材料，無需經本署審查或取得製造許可。

最終成品

牙科相關植入物，彌補物 神經學科相關植入物，固

定物 骨科相關如固定物，彌補

物，矯正裝置及植入物 手術器械 手術導板

手術模型 解剖構造模型

4. Standardization/Measurement

ASTM F42 Additive Manufacturing Technologies

ISO/TC 261 Additive Manufacturing

Support Action for Standardisation (SASAM) Project 2012

BSI AMT/8 Committee 2013

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4. Standardization/Measurement

30Image via ASTM

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4. Standardization/Measurement

The Roadmap Workshop on Measurement Science for Metal-Based Additive Manufacturing, May 2013

Thank you for your attention!

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