料 參 料 料 來 2

略 論 料 : 祥 94 年 11 24 1

料 參 料 料 來 2

3

料 (Biomedical materials) 料 療 料 參 料 來 Ratner, B. D. et al. Biomaterials Science: An Introduction to materials in medicine, 2nd ed., San Diego, Elsevier, 2004 4

料 (biomedical materials) 料 來 料 (biocompatibility) 來 行 料 念 (drug delivery system, DDS) 料 (biosensors) 料 療 料 5

料 (biomedical materials) 1. Clemson Advisory Board for Biomaterials 理 (implantation) (incorporation) 料 料 來 行 料 (biological material) (bone matrix) tooth enamel 2. 料 料 料 (nonviable material) 療 參 6

料 領 料 奈 若 料 來 類 類 利 來 料 理 料 料 7

料 料 2005 力 契 療 行 8

料 料 來 MIT,2005 9

料 類 料 料 類 來 類 Polymer Ceramic 金 Metal 料 composites 類 1. 金 料 療 臨 療 2. 料 料 3. 料 利 10

料 療 料 復 不 料 (regenerative medicine) 11

料 12

Number of yearly implant procedures in U.S. Type of procedure Number in million Bed sores 8.0 Breast prostheses 0.240 Burns 0.100 Corneal grafts 0.0369 Dental implant 0.045 Diabtic skin wounds 3.7 Fixation devices 0.100 Heart valves 0.43 Hip and knee implants 0.245 Intraocular lens 1.2 Skin excision 0.59 Tendon and ligament replacements 0.150 Total hip 0.170 Total knee 0.100 Vascular grafts 0.200 Vascular bypass grafts 0.194 13

2003 年 料 2003 年 料 484 2004 年 532 來 年 年 年 率 9~ 11% 料 若 52% 25% 13% 10% 見 料 料 若 料 44.6% 料 23.3% 料 18.3% 料 12.2% 料 1.6% 數 14

料 不 6 來 率 5% 4,600 來 年 率 15% 30% 來 量 料 諸 滑 料 料 料 料 力 奈 料 來 料 15

料 療 例 年 (US$)* ( ) 250 M** ( ) 200 M 40 M 30 M 2.5 M 0.5 M ( ) 0.25 M 0.9 M ( ) 0.3 M /CPB s ( 利 行 ) 0.3 M 0.3 M 律 ( ) 0.4 M 16

料 1. 力 料 良 2. 3. 年 勵 料 領 17

料 年 不 論 / (PLA) PLGA 料 料 露 來 降 料 立 GMP OEM 18

料 領 料 量 利 行 療 粒 料 臨 參 料 來 / 119 ITIS 19

料 林 北 料 糖 20

料 復 年 復 療 料 年 神 聯 金 PLGA/ / CSIRO 類 離 類 21

北 料 料 度 料 行 2D 3D 立 行 臨 料 度 料 靈 兩 料 靈 利 行 料 來 拓 22

猪 類 降 理 降 度 粒 都 列 23

料 煉 料 料 來 領 24

料 料 85 年 療 療 臨 料 92 年 4 8 料 勵 更 力 料 料 療 料 25

參 料 療 行 糖 立 量 / 量 / 量 量 量 類 料 26

料 料 料 料 糖 年 糖 立 行 料 / / 料 PGA ( ) / 27

立 聯 行 尿 / PLGA PDLLA PLLA 不 量 料 PDLLA 料 / Precimed 料 / 料 葉 / 28

立 聯 糖 行 立 Exactech ( ) / 北 料 / 29

聯 列 料 / 拓 金 立 / 30

料 料 (Collagen) 立 理 1. 1952 80.0(27.8) 2. 1998.12 立 3.0 3. 2002.10 金 2.0 4. 力 2000.2 8.0(6.85) 31

料 ( ) 立 理 1997 林 沈 隆 1.962 1998.11 4.80 2000 李 李 0.495 32

尿 (Hyaluronic acid, HA) 立 理 2002.11 3.35 金 2004.10 1.5 (0.7) 1997.6 金 4.0 (3.66) 33

- ( polyglutamate) 立 理 丹 1962.09 37.51 (polylactide, polygluconic acid) 立 理 1998 林 林 1.5 34

參 料 35

(chitin) 料 領 料 36

(Collagen) 量 量 20-30% 裡 量 (Polypeptides) 索 3000A 15A 索 量 300kDa 37

六 O 年 來 不 陸 便 了 類 38

類 歷 了 利 料 理 料 歷 O 年 90 年 連 都 了 更 料 度 猪 都 來 39

來 料 2010 年 料 料 類 1.0 3 4 料 4 5.5 8.5 10.5 料 40

年 不 41

( ) 見 來 行 不 便 10 30 4 年 了 列 料 年 來 類 42

不 不 21 不 量 量 90% 料 43

料 料 ( ) 料 ( 類 ) 料 ( ) 1 2 螺 3 聯 4 1 2 螺 3 聯 4 1 不 2 螺 3 4 料 料 料 料 料 4,000 /kg 50~60 /kg 1,200~1,800 /kg 44

料 1. 來 來 不 2. 3. 4. 拉 度 5. 6. 7. ( 粒 ) 8. 聯 理 度 9. 利 不 理 料 10. 料 更 45

料 聯 料 46

1. 2. 異 ( 例 聯 度 度 ) 3. 4. 度 度 異 5. 理 6. 例 (BSE) 料 來 C. H. Lee et al.:biomedical applications of collagen, International Journal of Pharmaceutics, vol. 221 (2001), pp.1-22 47

料 尿 療 神 神 料 來 http://www.hojo.com.tw/newc.htm 48

行 利 料 料 利 料 理 念 利 類 了 更 復 量 49

類 類 不 類 兩 螺 300 奈 1.5 奈 切 度 10 奈 0.5 奈 復 流 力 奈 糖 利 說 列 來 料 兩 類 50

尿 (Hyaluronic acid, HA) 料 不 理 料 療 領 51

2004 年 料 2004 年 11 (2005) 年 12 2010 年 年 8.1% 率 17 2001 年 5.64 2.65 47% 2.35 41.8% 1998 Supartz 料 20 來 力 52

1990 年 療 年 來 利 HA 不 不 力 HA 累 療 力 臨 落 53

HA HA HA 年 來 HA 料 HA (Collagen) 料 HA 類 料 (matrix) 類 / 料 料 HA 料 54

HA-based 料 神 (axon) (anti-scarring) HA 料 林 行 利 行 HA HA (dermal filler) 淚 料 利 領 55

例 奈 HA 離 不 省 力 力 更 了 立 奈 奈 料 56

料 類 料 (biodegradable polymer) 類 類 度 類 理 便 理 料 料 (ASTM) 料 ASTM D883-92 料 料 ISO 472( 料 ) 劣 57

料 料 (1) ( ) (2) ( 料 ) 力 降 (3) 裂 易 58

料 年 料 料 / 料 料 了 料 來 59

料 40 1994 年 量 30 70 2000 年 量 100 2010 年 北 量 200 1000 更 見 60

料 ($ ) 年 率 (%) 滑 4.251 7.8% 3.720 6.5% 0.938 54.3% 0.784 7.3% 0.594 6.6% 0.374 16.4% 料 0.215 8.3% 61

料 來 62

料 領 (tissue engineering) 料 FDA / PLGA 降 料 PEG polyethylene glycol 料 365nm 行 聯 10 泌 不 流 料 利 PLA PEG 狀 料 泌 料 降 留 63

bone marrow stromal cells Demineralized bone matrix calcium Sulfate/PLA composite) 40 料 都 利 GRGD 類 hyaluroninate MIT 行 mixing type 量 來 64

領 來 料 料 了 療 金 料 領 類 零 念 不 領 領 拓 不 料 切 料 領 路 若 力 療 65

老 療 來 料 利 料 路 料 不 異 例 力 路 臨 料 拓 陸 料 螺 泥 略 利 利 率 力 料 來 142 66

料 說 切 料 不 立 度 料 勵 料 21 流 67

參 料 1. 尿 離 93.11 2. -- 尿 93.11 3. -- 尿 羅 玲 玲 93.10 4. 93.07 5. 93.08 6. 93.08 7. 93.08 8. 料 -- 呂 93.0 9. 老 -- 劉 93.09 10. 93.08 11. 識 Collagen 93.04 12. 年 年?! 劉 93.04 13. 療 EBS-- ( ) 93.02 14. 料 92.06 15. 料 -- 92.02 16. 神 92.02 17. 料 -- 葉 91.12 18. 益 91.08 19. 料 利 林 90.06 20. 料 -- 李 89.10 21 尿 療 89.05 22. 猪 呂 89.03 68

23. 猪 呂 88.12 24. 猪 88.09 25. 料 祥 88.02 26. 猪 理 呂 87.12 27. ( ) 87.06 28. 87.03 29. 猪 率 呂 林 87.03 30. 猪 藍 糖 86.12 31. 連 力 李 86.06 32. ( ) 86.10 33. 86.08 34. 玲 85.07 35. 猪 呂 85.09 36. 聯 料 84.06 37. 利 料 84.04 38. -- 尿 (Hyaluronic acid) 83.05 69

E-mail: chchenj@biopharm.org.tw http://www.biopharm.org.tw 70

臨 Application of Synthetic BioMaterial in Clinical & Tissue Engineering 北 1 理 論 療 行 料 念 料 臨 料 2 1

65 老 年 來 3 Source: Health Care Financing Administration, Office of the Acluary, 2001 4 2

療 GDP(2002) [source: US CIA] US=US$10,400,000,000,000 [1] Taiwan=US$406,000,000,000 [23] 10.4 trillion 14.9% =1.55 trillion [US] 406 billion 3-5% =12-20 billion [Taiwan] (50%) (28%) (12%) (10%) 5 65 數 +96% +22% 6 3

+148% +103% 7 念 (Bio-compatibility) 療 (Medico-functionality) 8 4

(Anaphylaxie shock) 異 惡 (Allergie) 異 異 ( ) ( ) 9 料 10 5

Polyethylene 11 來 刺 料 來 刺 ( 理 ) 12 6

13 療 料 領 14 7

類 機 能 性 分 類 內 容 應 用 例 物 理 性 機 能 化 學 性 機 能 高 次 生 體 機 能 強 度 支 持 構 造 保 持 披 覆 閉 鎖 管 幫 浦 閥 電 氣 性 質 光 學 性 質 癒 合 充 填 物 質 移 動 選 擇 吸 著 化 學 計 測 化 學 反 應 生 體 機 能 人 工 骨 人 工 牙 根 人 工 關 節 損 傷 皮 膚 表 面 破 壞 組 織 閉 鎖 縫 合 線 釘 螺 絲 人 工 血 管 人 工 食 道 人 工 氣 管 轉 軸 catheter 心 律 調 整 器 人 工 感 覺 器 軟 式 隱 形 眼 鏡 眼 內 鏡 片 骨 水 泥 醫 療 用 接 著 劑 血 液 淨 化 人 工 肺 軟 式 隱 形 眼 鏡 人 工 肝 臟 吸 附 管 柱 生 物 檢 測 器 生 物 反 應 器 混 合 型 人 工 臟 器 15 療 料 (in vivo) (in vitro) (ex viv 理 理 16 8

料 類 類 料 17 類 Protein Polyamino acid NH H O C C R NH H O C C R Polysaccharide CH 2 OH O OR O Albumin, Fibrinogen (R=20 amino acid) Collagen Gelatin Polyglutamic acid (R=(CH 2) 2COOH) Polyleucine (R=CH 2CH(CH 3) 2) Polylysine (R=(CH 2 ) 4 NH 2 ) Amylose (R=H) (hydroxyethyl starch) (R=CH 2CH 2OH) ± ± peptidase proteinase chymotrypsin pepsin, papain, etc. amylase amino acid amino acid glucose OR COOH O OHHO CH 2OH O OH O O Dextran (R=H) Alginic acid Chitin (R=COCH 3 ) ± ± amylase lysozyme D-mannuronic acid L-guluronic acid N-acetylglucosamine Nucleic acid O P O O - O NHR O B Synthesized DNA (B: thymine, etc.) ± nuclease nucleoside phosphoric acid 18 9

類 ( ) Polyester Poly(α-hydroxy acid) O O CH C R n Poly(ω-hydroxycarbonic acid poly(glycollic acid) (R=H) poly(lactic acid) (R=Me) glycollic acid-co-lactic acid (polyglactin) malic acid (R=CH 2 COOH) copolymer lactide-caprolactone copolymer glycollic acid lactic acid malic acid O O CH 2 C x n O O CH 2 CH 2 C R n Poly(ester-ether) O O CH 2 CH 2 O CH 2 x C n poly-ε-caprolactone (x=5) poly-βhydroxycarbonate (R=Me, Et) polydioxanone (x=1) poly-1,4-dioxepan-7- one (x=2) ε-hydroxycaproric acid β-hydroxybutyrate hydroxyethyl carboxymethyl ether Poly(ester-carbonate) O O OCH 2 C OCH 2 CH 2 CH 2 O C x y n glycolide-trimethylene carbonate copolymer glycollic acid trimethylene glycol 19 類 ( ) Poly(acid anhydride) O C O CH 2 C x O n polysebacic anhydride (x=6) sebacic acid O C C 6 H 4 O O CH 2 C x O n poly-ω-(carboxyphenoxy) alkylate carboxylic anhydride alcohol Polyorthoester Et O O O O Et O CH 2 O x n alcohol Polycarbonate O poly-1,3-dioxan-2- O CH 2 O C trimethylene glycol x one (x=3) n 20 10

Poly lactic acid CH Polycondensation 3 CH 3 O HO CH COOH no Cat. H O CH C OH + nh 2 O n 20-5 mmhg, 180-240 C lactic acid lactic acid oligomer [M.W. < 10 4 ] Depolymerization Sb 2 O 3 5-1 mmhg, 250-270 C O C CH 3 O CH CH O H 3 C C O lactide Bulk ring opening polymerization (C7 H 15 COO) 2 Sn C 12 H 25 OH, 120-220 C(vac.) C 12 H 23 O CH 3 CH 3 C CH O C CH O O poly(lactic acid) [High M.W.] n OH 21 Bionolle ( ) PBS & PBSA CelGreen P-H( DaiCel ) Poly caprolactone H-(OCH 2 -CH 2 -CH 2 -CH 2 -CH 2 -COO) n -H Lunare SE( ) Poly(ethylene-co-succinate) 22 11

Properties of common biodegradable polymers Polymer Melting Point ( C) Glass- Transition Temp ( C) Modulus (GPa) a Degradation Time (months) b PGA 225-230 35-40 7.0 6 to 12 LPLA 173-178 60-65 2.7 >24 DLPLA Amorphous 55-60 1.9 12 to 16 PCL 58-63 (-65)- (-60) 0.4 >24 PDO N/A (-10)- 0 1.5 6 to 12 PGA-TMC N/A N/A 2.4 6 to 12 85/15 DLPLG Amorphous 50-55 2.0 5 to 6 75/25 DLPLG Amorphous 50-55 2.0 4 to 5 65/35 DLPLG Amorphous 45-50 2.0 3 to 4 50/50 DLPLG Amorphous 45-50 2.0 1 to 2 a Tensile or flexural modulus. b Time to complete mass loss. Rate also depends on part geometry. 23 24 12

CH 3 O CH CO COOH HO CH L-lactic acid CH 3 n hydrolysis NAD + NADH + + H + COOH C O ATP CH 3 CO 2 pyruvatic acid O CH CO CH 2 COOH n poly(malic acid) poly(l-lactide) CH 2 COSCoA ADP 2H hydrolysis COOH CH 2 HO C COOH CoA-SH CH 2 COOH citric acid COOH C O CH oxalacetic acid 2 COOH malic acid COOH HO CH CH 2 COOH H 2 O H 2 O COOH CH 2 C COOH HC COOH cis-aconitic acid PLLA 降 fumaric acid COOH CH HC COOH H 2 O COOH CH 2 C COOH HO CH COOH iso-citric acid α-ketoglutaric acid succinic acid COOH CH 2 CH 2 COOH 2H COOH CH 2 CH 2 C O COOH 25 CO 2 2H CO 2 2H 狀 不 狀 狀 Porogen 冷 26 13

拉 polycolide 不 27 冷 poly(l-lactide-co-εcarpolactone) 28 14

臨 ( ) 29 例 ( 金 ) 30 15

例 ( 金 ) 31 PLLA 臨 例 32 16

33 臨 ( ) 34 17

35 36 18

37 臨 ( ) 38 19

39 40 20

Sterilized, Freeze-Dried Amniotic Membrane: A Useful Substrate for Ocular Surface Reconstruction Investigative Ophthalmology & Visual Science, 2004 41 42 21

43 ( ) Cellular and nerve regeneration within a biosynthetic extracellular matrix for corneal transplantation May Griffith et.al. PNAS 2003 TERP5 copolymer Poly(N-isopropylacrylamide-coacrylic acidcoaryloxysuccinimide) PNiPAAm-coAAc-coASI 44 22

45 TERP5 46 23

利 切 (KLP) Lamellar keratoplasty (KLP) 47 臨 ( ) 48 24

( ) downgrowth 49 理 論 50 25

51 料 PLLA PGA HAp 52 26

53 理 BMP: BMP-2 BMP- 3 BMP-7(OP-1) Matrix (porous form), HAp, PLGA, PLLA, Collagen 54 27

( ) 55 ( ) 力 (scaffold) (frame work) 不 56 28

57 料 in vitro 2000 seeding 料 mesh 行 狀 1.5mm polyglycolic acid 狀 polylactin mesh 洞 率 95% 6-8 料 不 狀 狀 PCL-co- PLLA PGA or PLA fiber 58 29

PLGA 59 臨 ( ) 神 60 30

61 62 31

63 64 32

65 66 33

神 料 料 Glycolide trimethylene carbonate Polyester Polyglactin PGA PGA mesh coated with collagen PGA tube coated with collagen and filled with laminin-coated collagen fibers PLA Poly (organo) phosphazine Polyorthoester Copolymer of collagen and GAG Copolymer of L-lactide and caprolactone Copolymer of L-lactide and - caprolactone(inner layer) and a mixture of PU and PLA(outer layer) Rat Rat Mouse Rabbit Rabbit Monke y Monke y Rat Huma n Rabbit Cat Dog Mouse Rat Cat Rat Rat Rat 度 (mm) 5 5, 10, 20 3~13 7~9 10 1~1.5 30 5 5~30 30 25 80 4~5 10 15 10, 15 10 7 年 1992 1984 1985 1982 1983 1991 1988 1990,19 91 1990 1996 1995 2000 1985 1995 1987 1996 1993,19 96 1990 67 臨 ( 六 ) 68 34

69 Yannas ( chondroitin-6- sulphate) atelocollagen( ) (silicone film) 不 70 35

Integra(Yannas) 71 ( )GUNZE PELNAC (Collagen sponge) (Silicon sheet) 72 36

Dermagraft (Smith&Nephew, USA) Human Fibroblast-Derived Dermal Substitue mesh mesh 料 73 Trans Cyte (Advanced Tissue Sciences, USA) 龍 狀 (nylon mesh) 兩 不 74 37

75 76 38

( ) 數 臨 Apligraf 77 ( ) (gunze) PELNAC (Collagen sponge) (Silicon sheet) 78 39

類 Class I Class II Class III Class IV 說 若 不 良 狀 [ 例 ] 若 不 良 狀 [ 例 ]MRI 金 若 不 良 狀 [ 例 ] 若 不 良 狀 [ 例 ] 律 EU 度 度 FDA 度 JSA (--2005.4) JSA (2005.4--) 度 79 北 Tel: (02) 2736-1661 X 3228 Email: tsenghow@tmu.edu.tw 80 40

94 年 11 24 : 沈

參 臨 力 論

. 理 ( ) (Invitro diagnostic, IVD)

(Clinical) Chemistry Immuno assays Hemo to logy Microbiology Histology/Cytology Blood type

療 利 理 律 IP 利

參 立 1981 糖 Isotonic Buffer Solution Hgb Lyse Reagent For Hematology analyzer 1984 Heplitis B. C (Elisa) 1985 Heplitis B. C (Elisa) 1986 Clinical Chemistry Reagents 1980 Clinical Chemistry Reagents

糖 Cholesterol H Cholesterol L T.G. Uric Acid (Gaut) Clinical Chemistry Reagents T.B. Tunor Markers Cardiovascular POCP Reagents PSA Real Time PCR HPV Drug Abuse (Residure) 流 Biochips

Market share Genomic and proteomic fased assays

療 量 療 李 年 1

療 行 療 良 行 療 FDA 510(k) Premarket Notification Accredited Person FDA QSR/GMP Inspection Accredited Person Global Harmonization Task Force Study Group 4 Member Asian Harmonization Working Party Technical Committee 2

療 療 療 類 類 零 療 類 理 理 療 理 ( ) 3

療 療 Medical Device 料 療 In Vitro Diagnostic Medical Device 料 Tissue Engineered Product Combination Product 力 療 4

療 療 理 療 In Vitro Diagnostic Device, IVD 狀 狀 療 療 In Vitro Diagnostic Device, IVD 狀 狀 療 了 理 療 料 5

What is Medical Device Federal Food Drug & Cosmetic (FD&C) section 201(h) A device is "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: recognized in the official National Formulary, or the United States Pharmacopoeia,, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals,, or intended to affect the structure or any function of the body of man or other animals,, and which does not achieve any of it's primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes." 6

21 CFR 809.3 (a) In Vitro Diagnostic Device 療 療 狀 狀 療 聯 理 (Federal Food, Drug, and Cosmetic Act) 201( 201(h) h) 療 (Public Health Service Act) 351 351 (biological products) US FDA, Classification Names for Medical Devices and In Vitro Diagnostic Products FDA 列 IVD IVD 520 7

EU IVDD 98/79/EC 療 不 論 理 理 狀 異 療 療 不 論 不 療 列 療 令 令 不 行 不 行 立 料 療 不 令 8

IVDD 療 DNA probe 了 CE CE 令 療 9

療 93.4.21 93.8.31 不 良 93.11.26 93.12.2 93.12.31 療 理 93.12.31 療 1976 Food, Drug, and Cosmetic Act Medical Device Amendment 1995 Safe Medical Device Act 1997 Food and Drug Administration Modernization Act 2002 The Medical Device User Fee and Modernization Act 2000.1.14 療 理 例 2004.7.20 療 理 2004.8.9 療 理 陸 2004.8.9 療 理 2002.9.17 理 類 理 療 理 90/385/EEC Active Implanatable Medical Device Directive 93/42/EEC Medical Device Directive 98/79/EC In Vitro Diagnostic Medical Device Directive 10

行 療 89.5.16 93.8.31 不 良 93.4.21 93.10.22 93.11.26 93.12.2 93.12.31 療 理 93.12.31 療 11

Food Drug & Cosmetic Act Chapter 1 1 聯 理 Chapter 2 2 Chapter 3 3 Chapter 4 4 Chapter 5 5 療 501 不 良 療 502 不 良 療 503 療 量 510 療 Chapter 5( ) 513 療 514 Performance Standards 515 Premarket Approval 516 Banned Devices 517 Judicial Review 518 519 療 錄 520 療 522 Postmarket Surveillance 531~542 輻 12

療 令 Active Implantable Medical Devices Directive (90/385/EEC) Medical Device Directive (93/42/EEC) In-vitro Diagnostics Medical Devices Directive(98/79/EC) CE Marking Conformity Assessment Notified Body Harmonized CEN/EN/CENELEC Standards Vigilance System 13

療 EU EN ISO 13485 US Quality System Regulation 療 良 US Medical Device Reporting/Device Tracking/Post Market Surveillance EU Vigilance System / 不 良 POSTMARKET REPORTING QUALITY SYSTEM 理 PREMARKET REVIEW Registration/Listing 類 /US EU Classification US 510(k)/PMA 類 Good Clinical Practice/ISO 14155 療 US Investigational Device Exemption EU Conformity Assessment 14

1. / 2. 3. 療 4. 療 5. 臨 15

療 類 Type Class I Class II Class III 臨 臨 理 137 86 1 理 41 113 61 5 52 4 泌 尿 51 76 4 12 109 22 63 50 12 25 27 2 27 40 7 料 來 療 理 16

療 類 Type Class I Class II Class III 神 理 36 37 6 49 36 1 23 66 11 15 62 16 60 38 7 19 50 21 37 29 7 25 42 2 料 來 療 理 17

GMP I II III 數 量 733 861 128 GMP 不 ( ) + 臨 料 來 93.12 療 理 94.7 18

66~70 66~70 75 75 療 19

療 療 療 療 療 量 療 量 療 療 療 年 20

GMP GMP/QSD 量 金 / Class I 療 IVD II IVD 量 Class II/III 療 療 療 IVD GMP/QSD 錄 療 GMP 療 21

療 療 錄 說 療 切 療 料 料 療 類 料 療 良 理 論 料 臨 臨 錄 療 療 良 離 輻 輻 料 22

療 療 理 列 療 理 理 療 ( ) 23

療 臨 療 料 錄 療 臨 24

療 ( ) 療 療 25

Registration Listing Premarket Review Class I, II, III Premarket Notification 510(k) Premarket Approval Investigational Device Exemption 26

療 類 Class I 572(74%) 510(k) Class II 510(k) Class III PMA( 510(k)) scientific review Premarket Approval Establishment Registration Medical Device Listing labeling regulations in 21 CFR Part 801 or 809. special labeling requirements mandatory performance standards postmarket Special surveillance Controls GMP(QSR) according to 21 CFR 820 MDR General Controls 27

21 CFR Parts 862~892 862 Clinical chemistry and clinical toxicology devices 864 Hematology and pathology devices 866 Immunology and microbiology devices 868 Anesthesiology devices 870 Cardiovascular devices 872 Dental devices 874 Ear, nose, and throat devices 876 Gastroenterology-urology devices 878 General and plastic surgery devices 880 General hospital and personal use devices 882 Neurological devices 884 Obstetrical and gynecological devices 886 Ophthalmic devices 888 Orthopedic devices 890 Physical medicine devices 892 Radiology devices 28

Search Classification Database 29

Medical Device Establishment Registration and Listing Establishment Type Register List Manufacturer Remanufacturer Reprocessor Specifications Developer Repacker/Relabeler Contract Manufacturer - Domestic Contract Sterilizer - Domestic Initial Distributor/Importer Foreign establishment includes Foreign Exporter, Contract Manufacturer and Contract Sterilizer YES YES YES YES YES NO NO YES YES YES YES YES YES YES NO NO NO YES 30

FDA Labeling L Requirements 1. General Device Labeling Requirements (21 CFR 801.1, 801.4, 801.5, 801.6, 801.15) 2. Over the Counter (OTC) Devices (21 CFR 801.60, 801.61, 801.62) 3. Exemptions from Adequate Directions for use (Prescription Devices) (21 CFR 801.109) 4. Other Exemptions (21 CFR 801.110, 801.116, 801.119, 801.122, 801.125, 801.127) 5. Labeling for Specific Devices (21 CFR 801.405~437) 6. Misbranding (21 CFR 502(a)) 7. In Vitro Diagnostic Device Labeling Requirements (21 CFR 801.10) 8. Investigational Device Labeling Requirements 9. Quality System Regulation Labeling Requirements (21 CFR 801.150) 10. Radiation Emitting Device and Product Requirements 31

Premarket Notification, 510(k) A 510(k) is a premarketing submission made to FDA to demonstrate that the device to be marketed is as safe and effective, that is, substantially equivalent (SE), to a legally marketed device that is not subject to premarket approval(pma). Applicants must compare their 510(k) device to one or more similar devices currently on the U.S. market and make and support their substantial equivalency claims.. A legally marketed device is a device that was legally marketed prior to May 28, 1976 (preamendments( device), or a device which has been reclassified from Class III to Class II or I, a device which has been found to be substantially equivalent to such a device through the e 510(k) process, or one established through Evaluation of Automatic Class s III Definition. The legally marketed device(s) to which equivalence is drawn is known as the "predicate" device(s). 32

Premarket Notification, 510(k) Applicants must submit descriptive data and, when necessary, performance data to establish that their device is SE to a predicate device. Again, the data in a 510(k) is to show comparability, that is, substantial equivalency (SE) of a new device to a predicate device. 33

Special 510(k): Device Modification a manufacturer who is intending to modify his/her own legally marketed device 2 will conduct the risk analysis and the necessary verification and a validation activities to demonstrate that the design outputs of the modified device meet the design input requirements. Once the manufacturer has ensured the satisfactory completion of this process, a "Special 510(k): Device Modification" may be submitted. While the e basic content requirements of the 510(k) (21 CFR 807.87) will remain the t same, this type of submission should also reference the cleared 510(k) number 3 and contain a "Declaration of Conformity" with design control requirements. 34

Abbreviated 510(k) device manufacturers may choose to submit an Abbreviated 510(k) when: (1) a guidance documents exists, (2) a special control has been established, or (3) FDA has recognized a relevant consensus standard. 5 An Abbreviated 510(k) submission must include the required elements identified in 21 CFR 807.87. 35

510(k) Review Accredited Persons 36

Premarket Approval, PMA A Premarket Approval (PMA) application is a scientific, regulatory documentation to FDA to demonstrate the safety and effectiveness of the class III device. There are administrative elements of a PMA application, but good science and scientific writing is a key to the approval of PMA application. If a PMA application lacks elements listed in the administrative checklist, FDA will refuse to file a PMA application and will not proceed with the in-depth i review of scientific and clinical data. If a PMA application lacks valid clinical information and scientific ific analysis on sound scientific reasoning, it will delay FDA s s review and approval. PMA applications that are incomplete, inaccurate, inconsist,, omit critical information, and poorly organized have resulted in delays in approval or denial of PMA applications. Manufacturers should perform a quality control audit of a PMA application plication before sending it to FDA to assure that it is scientifically sound and presented in a well organized format. 37

The Medical Device User Fee and Modernization Act of 2002 FY 2006 Device Review User Fees (U.S. Dollars) Application Standard Fee Small Business ( $100 million in gross receipts or sales) Fee 510(k) $3,833 $3,066 Source: http://www.fda.gov/cdrh/mdufma/ufletterfy2006.htmlh 38

The Medical Device User Fee and Modernization Act of 2002 FY 2006 Device Review User Fees (U.S. Dollars) Application Premarket Application (PMA, PDP, BLA, PMR) NOTE: First premarket application from firms with gross receipts or sales $30 million Standard Fee $259,600 Fee is waived Small Business ( $100 million in gross receipts or sales) Fee $98,648 Panel-track Supplement $259,600 $98,648 Efficacy Supplement (for BLA) $259,600 $98,648 180-day Supplement $55,814 $21,209 Real-time Supplement $18,691 $7,103 39

Investigational Device Exemption, IDE An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device without complying with h other requirements of the Food, Drug, and Cosmetic Act (Act) that would d apply to devices in commercial distribution. Sponsors need not submit a PMA or Premarket Notification 510(k), register their establishment, or list the device while the device e is under investigation. Sponsors of IDE's are also exempt from the Quality System (QS) Regulation except for the requirements for design control. 40

98/79/EC EC IVD 類 Annex II List A: ABO ABO rhesus(c, c, E, e) anti-kell 量 HIV HIV (HIV1, 2) HTLV I, II B, C, D ISO 13485 or ISO 13488+Type-Examination 41

Annex II List B: 98/79/EC EC IVD 類 anti-duffy anti-kidd 異 anti anti-erythrocytic 量 rubella, toxoplasmosis congenital phenylketonuria cytomegalovirus, chlamydia HLA DR, A, B B PSA tumoral marker trisomy 21 糖 量 (self (self-diagnosis) diagnosis) 42

98/79/EC EC IVD 類 不 兩 類 療 糖 量 (self (self-testing) testing) 6 料 Annex II (devices for performance evaluation ) 錄 43

IVDD IVDD 44

IVDD IVDD 45

IVDD IVDD 46

IVDD IVDD Notified Body 47

IVDD IVDD A A.1 不 臨 臨 益 療 A.2 A.3 療 行 靈 度 (analytical sensitivity) 靈 度 (diagnostic sensitivity) 異 (analytical specificity) 異 (diagnostic specificity) 度 (accuracy) accuracy) (repeatability) repeatability) (reproducibility) reproducibility) 說 / 量 參 量 / 更 參 A.4 1, 3 3 不 類 A.5 料 ( 度 度 ) 不 不 良 48

IVDD IVDD B. B.1 理 B.1.1 療 量 料 不 B.1.2 療 降 漏 B.2 B.2.1 療 降 易 降 漏 B.2.2 料 料 (inactivation) (inactivation) (conservation) 來 降 B.2.3 (sterile) (sterile) 行 狀 B.2.4 B.2.5 了 度 不 理 料 降 B.2.6 良 B.2.7 度 不 49

IVDD IVDD B.3 B.3.1 療 連 不 B.3.2 降 連 料 B.3.3 降 力 理 理 力 度 度 B.3.4 降 暴 露 連 連 B.3.5 便 理 B.3.6 量 ( ) 50

IVDD IVDD B.4 量 B.4.1 量 參 量 參 量 量 精 度 精 度 精 度 B.4.2 量 數 量 B.5 輻 B.5.1 量 降 輻 暴 露 B.5.2 見 不 見 輻 輻 數 量 見 / B.5.3 輻 療 說 輻 51

IVDD IVDD B.6 連 B.6.1 度 B.6.2 降 B.6.3 B.6.4.4 B.6.4.1 不 力 力 零 落 零 不 52

IVDD IVDD B.6.4.2.4.2 降 B.6.4.3 降 B.6.4.4 力 連 降 B.6.4.5 連 零 ( 了 度 零 ) 不 度 B.7 量 量 異 說 易 了 B.7.1 行 易 易 量 降 讀 理 量 B.7.2 行 53

IVDD IVDD B.8 B.8.1 練 識 說 狀 說 / / 若 說 B.8.2 若 說 B.8.3 67/548/EEC 88/379/EEC 令 說 令 料 說 54

IVDD IVDD B.8 B.8.4 1. 2. 3. 說 狀 4. 列 5. 零 年 / / 6. 若 7. 8. 理 9. 10. 11. 55

IVDD IVDD B.8.5 說 說 B.8.6 離 零 便 B.8.7 說 a) 了 4, 5 5 b) 量 度 若 量 說 c) d).3.3 e) f) 說 g) 說 56

IVDD IVDD B.8.7 說 :( ) h) 量 理 靈 度 異 精 度 量 參 量 參 理 練 i) 數 j) 量 參 參 若 連 料 來 識 便 率 57

IVDD IVDD B.8.7 說 :( ) o) 理 p) q) 說 數 r) 暴 露 力 力 度 s) 不 (unusual risk) 來 類 t) o) 易 了 ( ) 若 了 省 略 不 療 若 練 行 療 說 行 58

Harminised Standards of AIMD, MDD, IVDD http://www.newapproach.org/directiveli st.asp 59

ISO 14971:2000 Annex G Overview of the risk management process ISO 9001 ISO 9000-3 ISO 10993-1 ISO 13485 Applicable standards ISO 14969 IEC 60300-3-9 IEC/TR 60513 IEC 60601-1-4 IEC 60812 IEC 61025 EN 12442-1 Scope identification Risk analysis Hazard identification Risk estimation Risk evaluation Analysis of options Risk control Decision making Implementation Post production information Indicates the parts of the risk management process which might be related to these International Standards 60

療 EU EN ISO 13485 US Quality System Regulation 療 良 US Medical Device Reporting/Device Tracking/Post Market Surveillance EU Vigilance System / 不 良 POSTMARKET REPORTING 理 QUALITY SYSTEM PREMARKET REVIEW Registration/Listing 類 /US EU Classification US 510(k)/PMA 類 Good Clinical Practice/ISO 14155 療 US Investigational Device Exemption EU Conformity Assessment 61

GMP GMP/QSD 量 金 / Class I 療 IVD II IVD 量 Class II/III 療 療 療 IVD GMP/QSD 錄 療 GMP 療 62

療 良 復 料 理 例 行 --- 63

良 六 療 良 六 Harmonized with ISO 13485:1996 64

ISO 14971:2000 Annex G Overview of the risk management process Subclauses of ISO 13485:1996 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 General requirements Scope identification Risk analysis Hazard identification Risk estimation Risk evaluation Analysis of options Risk control Decision making Implementation Post production information Note 1: Risk management can be part of a quality management system. Note 2: The risk management file can include quality records. Indicates the parts of the risk management process which might be related to these International Standards 65

連 ( ) 料 行 ( ) 良 療 良 ( ) 列 ( ) 良 療 良 療 臨 良 66

IVD GMP Class III Class I, II 療 良 67

量 金 68

療 QSD QSD 流 療 QSD QSD FDA EIR? 療 EIR: Establishment Inspection Report; FDA GMP QSD ISO 13485 流 QSD 69

Quality System Regulation/ Good Manufacturing Practice US FDCA Medical Device Amendment of 1976 section 520(f) authorized Good Manufacturing Practice requirements FDA issued final rules of GMP in Federal Register of July 21, 1978 (43 FR 31508), effective on December 18, 1978 as 21 CFR 820 1990 Safe Medical Devices Act of 1990 (SMDA) amended FDCA section n 520(f) to provide FDA with the authority to add preproduction design controls to the GMP regulation and encouraged FDA toward mutual recognition November 30 1990, Federal Register Medical Devices: Current Good Manufacturing Practices (CGMP) Regulations Document; Suggested Changes, C Availability November 23 1993, Federal Register First proposed rule revising the GMP July 1995, Notice of Availability of a Working Draft of the CGMP Final Rule 70

Quality System Regulation/ Good Manufacturing Practice 1995 CGMP/Quality System Regulation (QSR) vs. 1978 GMP 1978 GMP critical device: devices that are intended for surgical implant into the body or devices intended to support or sustain life and whose failure to perform when properly used according to the labeling can be reasonably expected to result in significant injury to the user was eliminated in the QSR Preproduction design control was added to QSR Supplier control was added to QSR Servicing control was added to QSR Management responsibilities, process validation, corrective and preventive action, quality system records, and statistical technique is explicit in QSR. Although already inherent in 1978 GMP Harmonized with ISO 13485:1996 71

QSR vs. ISO 13485: 1996 ISO 13485 TITLE QSR 4.1 Management Responsibility 820.20 4.2 Quality System Principles 820.5 4.3 Contract or Purchase Order Review 820.160 4.4 Design Control 820.30 4.5 Document Control 820.40 4.6 Purchasing 820.50 4.7 Purchaser Supplied Product NA 4.8 Device Identity and Traceability 820.60-65 4.9 Process Control 820.70 4.10 Inspection and Testing 820.80 4.11 Inspect, Measuring & Test Equipment 820.72 4.12 Inspection and Test Status 820.86 4.13 Control of Nonconforming Devices 820.90 4.14 Corrective Action 820.100 4.15 Handle, Store, Package & Deliver 820.130-.170 4.15 Labeling 820.120 4.16 Quality Records 820.186 4.17 Internal Quality Audits 820.22 4.18 Training 820.25 4.19 Complaint Handling 820.186 4.19 Servicing 820.200 4.20 Statistical Techniques 820.250 72

EU IVDD 98/79/EC GENERAL IVD DEVICES OTHER THAN DEVICES FOR SEFL TESTING OR DEVICES APPEARING IN ANNEX II Device Annex II EC Declaration of Conformity CE Mark Annex IV Full Quality Assurance (EN ISO 13485) Audit by Notified Body SEFL TESTING IVD s EXCLUDING THOSE WHICH APPERA IN ANNEX II Annex VI EC Verification (Product Examination) by Notified Body Device Annex V EC Type Examination by Notified Body Annex VII Production Quality Assurance (EN ISO 13485) Audited by Notified Body Annex III IVDMDD EC Declaration of Conformity Product Design Examination (Annex III Section 6) by Notified Body CE Mark IVD s APPEARING IN ANNEX II LIST B IVD s APPEARING IN ANNEX II LIST A Device Device Annex IV Full Quality Assurance (EN ISO 13485) Audit by Notified Body Annex VI EC Verification (Product Examination) By Notified Body Annex V EC Type Examination by Notified Body Annex VII Production Quality Assurance (EN ISO 13485) Audit by Notified Body Annex IV Full Quality Assurance (EN ISO 13485) Audit by Notified Body Product Design Dossier Examination (Annex IV Section 4) By Notified Body Batch or Product Verification (Annex IV Section 6) by Notified Body Annex V EC Type Examination by Notified Body Annex VII Production Quality Assurance (EN ISO 13485) Audit by Notified Body Batch or Product Verification (Annex VII Section 5) by Notified Body CE Mark CE Mark 73

ISO 9001 ISO 13485 QSR? ISO 9001:2000 流 ISO 13485 2003 流 QSR QSR ISO 13485:1996 ISO 13485: 1996 流 FD&C Act QSR FDA 不 讀 QSR+Preamble 了 QSR QSR ISO 13485:2003 異 理 74

療 EU EN ISO 13485 US Quality System Regulation 療 良 US Medical Device Reporting/Device Tracking/Post Market Surveillance EU Vigilance System / 不 良 POSTMARKET REPORTING QUALITY SYSTEM 理 PREMARKET REVIEW Registration/Listing 類 /US EU Classification US 510(k)/PMA 類 Good Clinical Practice/ISO 14155 療 US Investigational Device Exemption EU Conformity Assessment 75

1. 療 GMP/QSD 錄 3 年 2. 療 5 年 3. 療 4. 不 76

列 劣 不 良 療 療 列 益 不 77

列 行 立 列 理 更 六 六 療 78

不 良 不 良 療 不 良 列 不 良 六 79

不 良 療 不 良 料 料 料 不 不 良 80

FDA Postmarket Requirements Recalls Corrections and Removals Postmarket Surveillance Device Tracking Medical Device Reporting, MDR 81

Medical Device Reporting for Manufacturers Baseline reports for devices that have been reported in individual adverse event reports Death, serious injury and malfunction adverse event reports within 30 calendar days Supplemental reports within 30 calendar days of receipt of information 5-day reports within 5 work days (work days refers to any day Monday-Friday, excluding Federal holidays) 82

Medical Device Reporting, MDR REPORTER WHAT TO REPORT REPORT FORM # Manufacture r 30 day reports of deaths, serious injuries and malfunctions Form FDA 3500A TO WHOM FDA WHEN Within 30 calendar days from becoming aware of an event 5-day reports on events that require remedial action to prevent an unreasonable risk of substantial harm to the public health and other types of events designated by FDA 83

Medical Device Reporting, MDR REPORTER WHAT TO REPORT REPORT FORM # Manufacture r Baseline reports to identify and provide basic data on each device that is subject of an MDR report. At this time, FDA has stayed the requirement for denominator data requested in Part II, Items 15 and 16 on Form 3417. TO WHOM Form FDA 3417 FDA WHEN With 30 calendar, and 5 work day reports when device or device family is reported for the first time. Interim and annual updates are also required if any baseline information changes after initial submission. 84

Medical Device Reporting, MDR REPORTER WHAT TO REPORT REPORT FORM # User Facility Death Form FDA 3500A TO WHOM FDA & Manufactur er WHEN Within 10 work days Serious injury Form FDA 3500A Manufactur er. FDA only if manufactur er unknown Within 10 work days Annual reports of death & serious injury Form FDA 3419 FDA January 1 85

Medical Device Reporting, MDR REPORTER WHAT TO REPORT REPORT FORM # Annual Certification Manufacture r TO WHOM Form FDA 3381 FDA WHEN Coincide with firm's annual registration dates. The reporting changes are: Medical device manufacturers, importers, and distributors are no longer required to submit an annual certification statement. Domestic distributors no longer have to submit MDR reports, but they must continue to maintain records of adverse events. Importers continue to be subject to the remaining requirements of the MDR regulation, 21 CFR 803. User facilities now submit a report annually instead of semi-annually. 86

陸 療 療 理 例 ( 令 276 276 2000/1/14) 療 臨 理 令 5 2000/2/9 療 說 識 理 令 10 10 2004/7/8 療 理 ( 令 12 12 2004/7/20) 療 理 令 15 15 2004/8/9 療 理 ( 令 16 16 2004/8/9) 理 類 理 2002 324 2002/9/17 療 理 87

療 理 理 2004 年 8 9 行 療 理 ( 理 令 16 16 ) 陸 療 理 療 類 療 4 年 6 88

陸 療 類 類 類 理 省 理 理 ( ) 理 89

陸 療 理 類 類 療 理 量 行 行 療 臨 行 臨 理 量 療 理 理 年 療 90

類 理 行 類 理 行 理 類 療 行 理 律 理 類 行 理 1 類 2 類 3 類 4 類 5 類 類 6 類 7 類 91

類 理 療 理 1 臨 類 2 臨 類 3 類 4 類 5 類 6 類 7 類 92

類 理 理 療 行 類 理 療 理 例 省 理 療 行 療 類 行 93

類 理 六 類 療 理 2003 年 12 31 31 療 行 療 2002 年 10 1 理 不 理 療 理 年 療 2004 年 7 1 不 94

陸 (2005.10) 理 65 65 30 30 療 GMP GMP 類 錄 95

療 理 1. 臨 2. 臨 3. 臨 4. 5. 6. 7. 8. 9. 96

理 1. ABO * 2. HBsAg HBsAg * 3. HCV HCV * 4. 類 HIV HIV 1 2 * 5. 類 / 6. 螺 * 7. ( ) * 理 臨 類 療 行 理 97

Global Harmonization Task Force 1. Study Group 1 Premarket Effectiveness and safety evaluation, role of standards, classification, cation, labelling,, technical documentation 2. Study Group 2 Postmarket Adverse event reporting postmarket surveillance 3. Study Group 3 Quality System Quality system guidelines, design control, process validation, risk r management 4. Study Group 4 Auditing General guidelines for regulatory auditing, audit language, audit t strategy, audit report, audit documentation 5. Study Group 5 Clinical Evaluation 98

療 療 Study Group 1 Study Group 3 臨 理 Study Group 4 Study Group 5 Study Group 2 療 99

療 SG1-N29R16:2005: Definition of medical device 療 SG1/N015R22: Classification SG1-N41R9:2005: Essential principles SG1(PD)/N043R6: Labelling 100

SG 5 臨 SG1/N044R4: Standards 理 SG1/N011R17: Summary of Technical File 療 101

SG2/N31R8: Report of User Error SG2/N32R5: Data Set for Adverse Event Report SG2/N20R10: Report Exchange SG2/N7R11: Minimum Data Set for Adverse Event Report 療 SG2/N36R7: Trend Reporting for Adverse Event SG2/N9R11: Competent Authority Report SG2/N33R11: Timing for Adverse Event Report SG2/N6R3: Adverse Event Reporting System Comparison SG2/N8R4: How to Handle Information SG2/N21R8: Adverse Event Reporting Guidance SG2/N38R15: Report exchange program 療 102

療 療 SG3/N99-8: Quality System for Design and Manufacture SG3/N99-10 (Edition 2):Process Validation 臨 理 SG3 N99-9: Design Control Process SG3/N15R8/2005: Risk Management 103

SG4(00)3: Training Requirements for Auditors SG4(99)14:Audit Language SG4(99)28: General Requirements for Auditing SG4N(99)24R3: Compilation of Audit Documentation SG4/N30R10: Regulatory Audit Strategy SG4N26R1:Observed Audit 臨 理 若 立 療 104

GHTF Study Group 2 Postmarket Study Group 3 Quality System Study Group 4 Auditing Study Group 5 Clinical Evaluation STED STED Classification 列 臨 Performance Performance 異 105

World Health Organization, Medical Device Regulations: Global Overview and Guiding Principles, 2003, http://www.who.int/medical_devices/publications/en/md_regulations.pdf s.pdf 療 http://medical.cms.itri.org.tw 行 http://www.doh.gov.tw Global Harmonization Task Force http://www.ghtf.org Asian Harmonization Working Party: http://www.asiahwp/org US FDA: http://www.fda.gov/cdrh www.fda.gov/cdrh/ EU Medical Device: http://europa.eu.int/comm/enterprise/medical_devices/index.htm Japan MHLW: http://www1.mhlw.go.jp/ Canada TPP: http://www.hc-sc.gc.ca/hpfb sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_devices_e.htmldpt/index_devices_e.html Australia TGA: http://www.tga.gov.au China SFDA: http://www.sda.gov 106