料 參 料 料 來 2

Transcription

1 略 論 料 : 祥 94 年

2 料 參 料 料 來 2

3 3

4 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,

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

6 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

7 料 領 料 奈 若 料 來 類 類 利 來 料 理 料 料 7

8 料 料 2005 力 契 療 行 8

9 料 料 來 MIT,2005 9

10 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

11 料 療 料 復 不 料 (regenerative medicine) 11

12 料 12

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

14 2003 年 料 2003 年 料 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

15 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

16 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

17 料 1. 力 料 良 年 勵 料 領 17

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

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

20 料 林 北 料 糖 20

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

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

23 猪 類 降 理 降 度 粒 都 列 23

24 料 煉 料 料 來 領 24

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

26 參 料 療 行 糖 立 量 / 量 / 量 量 量 類 料 26

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

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

29 立 聯 糖 行 立 Exactech ( ) / 北 料 / 29

30 聯 列 料 / 拓 金 立 / 30

31 料 料 (Collagen) 立 理 (27.8) 立 金 力 (6.85) 31

32 料 ( ) 立 理 1997 林 沈 隆 李 李

33 尿 (Hyaluronic acid, HA) 立 理 金 (0.7) 金 4.0 (3.66) 33

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

35 參 料 35

36 (chitin) 料 領 料 36

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

38 六 O 年 來 不 陸 便 了 類 38

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

40 來 料 2010 年 料 料 類 料 料 40

41 年 不 41

42 ( ) 見 來 行 不 便 年 了 列 料 年 來 類 42

43 不 不 21 不 量 量 90% 料 43

44 料 料 ( ) 料 ( 類 ) 料 ( ) 1 2 螺 3 聯 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

45 料 1. 來 來 不 拉 度 ( 粒 ) 8. 聯 理 度 9. 利 不 理 料 10. 料 更 45

46 料 聯 料 46

47 1. 2. 異 ( 例 聯 度 度 ) 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

48 料 尿 療 神 神 料 來 48

49 行 利 料 料 利 料 理 念 利 類 了 更 復 量 49

50 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

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

52 2004 年 料 2004 年 11 (2005) 年 年 年 8.1% 率 年 % % 1998 Supartz 料 20 來 力 52

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

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

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

56 例 奈 HA 離 不 省 力 力 更 了 立 奈 奈 料 56

57 料 類 料 (biodegradable polymer) 類 類 度 類 理 便 理 料 料 (ASTM) 料 ASTM D 料 料 ISO 472( 料 ) 劣 57

58 料 料 (1) ( ) (2) ( 料 ) 力 降 (3) 裂 易 58

59 料 年 料 料 / 料 料 了 料 來 59

60 料 年 量 年 量 年 北 量 更 見 60

61 料 ($ ) 年 率 (%) 滑 % % % % % % 料 % 61

62 料 來 62

63 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

64 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

65 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

66 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

67 料 說 切 料 不 立 度 料 勵 料 21 流 67

68 參 料 1. 尿 離 尿 尿 羅 玲 玲 料 -- 呂 老 -- 劉 識 Collagen 年 年?! 劉 療 EBS-- ( ) 料 料 神 料 -- 葉 益 料 利 林 料 -- 李 尿 療 猪 呂

69 23. 猪 呂 猪 料 祥 猪 理 呂 ( ) 猪 率 呂 林 猪 藍 糖 連 力 李 ( ) 玲 猪 呂 聯 料 利 料 尿 (Hyaluronic acid)

70 70

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

72 65 老 年 來 3 Source: Health Care Financing Administration, Office of the Acluary,

73 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

74 +148% +103% 7 念 (Bio-compatibility) 療 (Medico-functionality) 8 4

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

76 Polyethylene 11 來 刺 料 來 刺 ( 理 ) 12 6

77 13 療 料 領 14 7

78 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

79 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

80 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

81 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, C lactic acid lactic acid oligomer [M.W. < 10 4 ] Depolymerization Sb 2 O mmhg, 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, 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

82 Properties of common biodegradable polymers Polymer Melting Point ( C) Glass- Transition Temp ( C) Modulus (GPa) a Degradation Time (months) b PGA to 12 LPLA >24 DLPLA Amorphous to 16 PCL (-65)- (-60) 0.4 >24 PDO N/A (-10) to 12 PGA-TMC N/A N/A to 12 85/15 DLPLG Amorphous to 6 75/25 DLPLG Amorphous to 5 65/35 DLPLG Amorphous to 4 50/50 DLPLG Amorphous to 2 a Tensile or flexural modulus. b Time to complete mass loss. Rate also depends on part geometry

83 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

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

85 臨 ( ) 29 例 ( 金 ) 30 15

86 例 ( 金 ) 31 PLLA 臨 例 32 16

87 33 臨 ( ) 34 17

88

89 37 臨 ( ) 38 19

90

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

92 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

93 45 TERP

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

95 ( ) downgrowth 49 理 論 50 25

96 51 料 PLLA PGA HAp 52 26

97 53 理 BMP: BMP-2 BMP- 3 BMP-7(OP-1) Matrix (porous form), HAp, PLGA, PLLA, Collagen 54 27

98 ( ) 55 ( ) 力 (scaffold) (frame work) 不 56 28

99 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

100 PLGA 59 臨 ( ) 神 60 30

101

102

103

104 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~ ~ ~ , 年 , , 臨 ( 六 ) 68 34

105 69 Yannas ( chondroitin-6- sulphate) atelocollagen( ) (silicone film) 不 70 35

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

107 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

108

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

110 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 ( ) JSA ( ) 度 79 北 Tel: (02) X [email protected] 80 40

111 94 年 : 沈

112 參 臨 力 論

113 . 理 ( ) (Invitro diagnostic, IVD)

114

115

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

117 療 利 理 律 IP 利

118

119

120

121

122 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

123

124

125

126

127

128

129 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

130

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132 Market share Genomic and proteomic fased assays

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134 療 量 療 李 年 1

135 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

136 療 療 療 類 類 零 療 類 理 理 療 理 ( ) 3

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

138 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

139 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

140 21 CFR (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) (biological products) US FDA, Classification Names for Medical Devices and In Vitro Diagnostic Products FDA 列 IVD IVD 520 7

141 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

142 IVDD 療 DNA probe 了 CE CE 令 療 9

143 療 不 良 療 理 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 療 理 例 療 理 療 理 陸 療 理 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

144 行 療 不 良 療 理 療 11

145 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 療 錄 520 療 522 Postmarket Surveillance 531~542 輻 12

146 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

147 療 EU EN ISO 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 療 US Investigational Device Exemption EU Conformity Assessment 14

148 1. / 療 4. 療 5. 臨 15

149 療 類 Type Class I Class II Class III 臨 臨 理 理 泌 尿 料 來 療 理 16

150 療 類 Type Class I Class II Class III 神 理 料 來 療 理 17

151 GMP I II III 數 量 GMP 不 ( ) + 臨 料 來 療 理

152 66~70 66~ 療 19

153 療 療 療 療 療 量 療 量 療 療 療 年 20

154 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

155 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

156 療 療 理 列 療 理 理 療 ( ) 23

157 療 臨 療 料 錄 療 臨 24

158 療 ( ) 療 療 25

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

160 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

161 21 CFR Parts 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

162 Search Classification Database 29

163 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

164 FDA Labeling L Requirements 1. General Device Labeling Requirements (21 CFR 801.1, 801.4, 801.5, 801.6, ) 2. Over the Counter (OTC) Devices (21 CFR , , ) 3. Exemptions from Adequate Directions for use (Prescription Devices) (21 CFR ) 4. Other Exemptions (21 CFR , , , , , ) 5. Labeling for Specific Devices (21 CFR ~437) 6. Misbranding (21 CFR 502(a)) 7. In Vitro Diagnostic Device Labeling Requirements (21 CFR ) 8. Investigational Device Labeling Requirements 9. Quality System Regulation Labeling Requirements (21 CFR ) 10. Radiation Emitting Device and Product Requirements 31

165 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

166 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

167 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 ) 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

168 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

169 510(k) Review Accredited Persons 36

170 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

171 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: 38

172 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, day Supplement $55,814 $21,209 Real-time Supplement $18,691 $7,103 39

173 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

174 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 or ISO Type-Examination 41

175 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

176 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

177 IVDD IVDD 44

178 IVDD IVDD 45

179 IVDD IVDD 46

180 IVDD IVDD Notified Body 47

181 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

182 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

183 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

184 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

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

186 IVDD IVDD B 降 B 降 B 力 連 降 B 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

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

188 IVDD IVDD B.8 B 說 狀 4. 列 5. 零 年 / / 6. 若 理

189 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

190 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

191 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

192 Harminised Standards of AIMD, MDD, IVDD st.asp 59

193 ISO 14971:2000 Annex G Overview of the risk management process ISO 9001 ISO ISO ISO Applicable standards ISO IEC IEC/TR IEC IEC IEC EN 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

194 療 EU EN ISO 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 療 US Investigational Device Exemption EU Conformity Assessment 61

195 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

196 療 良 復 料 理 例 行

197 良 六 療 良 六 Harmonized with ISO 13485:

198 ISO 14971:2000 Annex G Overview of the risk management process Subclauses of ISO 13485: 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

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

200 IVD GMP Class III Class I, II 療 良 67

201 量 金 68

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

203 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 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 , Federal Register Medical Devices: Current Good Manufacturing Practices (CGMP) Regulations Document; Suggested Changes, C Availability November , Federal Register First proposed rule revising the GMP July 1995, Notice of Availability of a Working Draft of the CGMP Final Rule 70

204 Quality System Regulation/ Good Manufacturing Practice 1995 CGMP/Quality System Regulation (QSR) vs 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:

205 QSR vs. ISO 13485: 1996 ISO TITLE QSR 4.1 Management Responsibility Quality System Principles Contract or Purchase Order Review Design Control Document Control Purchasing Purchaser Supplied Product NA 4.8 Device Identity and Traceability Process Control Inspection and Testing Inspect, Measuring & Test Equipment Inspection and Test Status Control of Nonconforming Devices Corrective Action Handle, Store, Package & Deliver Labeling Quality Records Internal Quality Audits Training Complaint Handling Servicing Statistical Techniques

206 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

207 ISO 9001 ISO QSR? ISO 9001:2000 流 ISO 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

208 療 EU EN ISO 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 療 US Investigational Device Exemption EU Conformity Assessment 75

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

210 列 劣 不 良 療 療 列 益 不 77

211 列 行 立 列 理 更 六 六 療 78

212 不 良 不 良 療 不 良 列 不 良 六 79

213 不 良 療 不 良 料 料 料 不 不 良 80

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

215 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

216 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

217 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 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

218 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

219 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

220 陸 療 療 理 例 ( 令 /1/14) 療 臨 理 令 /2/9 療 說 識 理 令 /7/8 療 理 ( 令 /7/20) 療 理 令 /8/9 療 理 ( 令 /8/9) 理 類 理 /9/17 療 理 87

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

222 陸 療 類 類 類 理 省 理 理 ( ) 理 89

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

224 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

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

226 類 理 理 療 行 類 理 療 理 例 省 理 療 行 療 類 行 93

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

228 陸 ( ) 理 療 GMP GMP 類 錄 95

229 療 理 1. 臨 2. 臨 3. 臨

230 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

231 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

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

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

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

235 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

236 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

237 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

238 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

239 World Health Organization, Medical Device Regulations: Global Overview and Guiding Principles, 2003, s.pdf 療 行 Global Harmonization Task Force Asian Harmonization Working Party: US FDA: EU Medical Device: Japan MHLW: Canada TPP: sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_devices_e.htmldpt/index_devices_e.html Australia TGA: China SFDA: 106