如何利用采认标准资料库进行产品设计开发之依据指.doc

計畫名稱：推動醫療器材標準採認機制及其產業應用計畫產出：如何利用採認標準資料庫進行產品設計開發之依據指導手冊草稿如何利用採認標準資料庫進行產品設計開發之依據指導手冊草稿撰稿單位：工研院量測中心醫療器材驗證室日期：95年11月10日1 引言本文件旨在提供一完整的醫療器材安全及功效評估之方法，協助製造廠商在設計開發階段導入國際醫療器材法規及相關標準之要求，以增加國際競爭力。本文件提供的方法係從醫療器材的基本安全考量之寬廣面漸漸收攝到以產品類別/族群安全與功效評估之有限面，最終匯聚到個別產品的特殊安全與功效的焦點，並以將以範例展現此思路。此等範例的提出亦為未來我國醫療器材標準採認皆是可能之工作方向。2 理據全球化的浪潮不斷地衝擊著醫療器材的市場，要想拓展全球市場，本土廠商必須以宏觀的標準化視野來審視產品的安全及功效，讓產品不僅能符合國內的醫療器材法規，更能符合廣大的外銷市場。3 範圍、方法概述、美國上市前審查之醫材安全及功效評估3.1 範圍全球醫療器材法規的調和化已行之有年，其代表組織有全球調和化工作小組 (Global Harmonization Task Force，簡稱GHTF)，該組織自成立以來即致力於制定醫療器材標準化以及安全與功效的評估之指引，以供衛生主管機關、製造廠商及認證機構等參考遵循。該組織之第1考察團 (Study Group 1，簡稱SG1) 於2005年5月20日公佈之指引GHTF/SG1/N41R9:2005 醫療器材之安全與功效基本準則(“Essential Principles of Safety and Performance of Medical Devices”) 即參考歐盟醫療器材指令附件中之安全及功效基本要求 (Essential Requirements)，提出17條基本準則 (Essential Principles) ，討論醫療器材設計開發時所需注意之風險及相關標準。此指引配合該組織所推動的簡易技術文件檔案 (Summary Technical Documentation，簡稱 STED) 審查模式，廣泛為美國、加拿大、歐盟、澳洲、日本等國所接受，蔚然成為評估醫療器材安全與功效的利器。3.2 方法概述我國歷來外銷美國的醫療器材皆在當地有相當之市佔率，是以我國有不少醫療器材製造廠商對申請美國醫療器材之上市前通知 (Premarket Notification，又稱510(k) Submission) 有著豐富的經驗，對美國的食品、藥物及化妝品法 (Food, Drug & Cosmetic Act) 也並不陌生。該法第 514 條即建議，製造廠商可以利用標準組織制定之功效性標準 (Performance Standard) 作為設計開發時安全與功效之參考，並採用與產品相關的，經衛生主管機關採認之標準。是故製造廠商若能採用這些標準，同時配合與已上市產品之功能性比對，將有助加快審查程序。本文件建議調合 GHTF 安全及功效基本準則、美國食品藥物及化妝品管制局（Food, Drug and Cosmetic Administration，簡稱FDA）建議之採認標準與相關指引以及我國醫療器材採認標準查詢資料庫，作為產品上市前安全及功效評估之工具。製造廠商必須建立以程序為本的品質管理系統，從產品的特性出發，考慮GHTF安全及功效基本準則中提及之風險因子，並盡可能將其消除或降至最低。 同時，針對產品特有的功效特徵，廠商則可參考美國 FDA 認可之採認標準與相關之指引以及我國醫療器材採認標準查詢資料庫，採用合適的垂直標準以為符合性評估之依據。3.3 美國上市前審查之醫材安全及功效評估惟廠商若要外銷美國，除了以上所述的標準符合性評估以外，更必須令訓練精良的工作人員在以程序為本的品質管理系統當中，採用當代科學思潮 (State of the art) 的技術，進行產品功效的評估及特殊品質管控，將有助於產品之實質相等性的確立。以下舉例說明：以非侵入式血壓監測系統 (血壓計) 之功能性評估為例，廠商需以基本準則為本尋找相關之特殊功能性標準，並根據該器材之功能性特徵，參考該標準訂出器材之規格，然後與已上市器材做比較，綜合判斷該器材之實質相等性。(因篇幅有限，此處以一器材、一基本準則、一特殊功能性標準及相關功能性特徵為例示意，讀者應舉一反三。)基本準則特殊功能性標準器材比對實質相等性判斷申請器材已上市器材5.13 機械性及熱力風險5.13.4 使用者操作的電源連接埠及連接端、氣體及氣壓式能量供源之設計與製造必須將所有可能風險降至最低。5.13.5 可供使用的器材零件 (不包含供給熱或達致設定溫度者) 及其週邊在正常使用情況下不能達到具潛在危險的溫度。ANSI/AAMI SP 10:2002 (Manual, electronic or automated sphygmomanometers)4.3.1.1 PX1000 software will automatically deflate the cuff when the cuff pressure exceeds 300 mmHg. Likewise, when the pressure within cuff exceeds 10 mmHg for more than 5 minutes, the cuff will also be deflated.4.3.1.2 The user could enable emergency stop or cuff exhaust by pushing any button during measuring.For the ambient temperature 0 10, 20, 40 and humidity of 10%95 (non-condensing), the difference of the cuff pressure indication doesnt exceed 3 mmHg.4.3.1.1 HEM-7 software will automatically deflate the cuff when the cuff pressure exceeds 300 mmHg. Likewise, when the pressure within cuff exceeds 10 mmHg for more than 5 minutes, the cuff will also be deflated.4.3.1.2 The user could enable emergency stop or cuff exhaust by pushing any button during measuring.For the ambient temperature 0 10, 20, 40 and humidity of 10%85 (non-condensing), the difference of the cuff pressure indication doesnt exceed 3 mmHg.SESE SE功能性特徵4.3.1 device with automatic inflation systems4.3.1.1 maximum cuff pressure4.3.1.2 cuff deflation4.2.2 operating conditionsa) a range in temperature of 10 to 40b) a range in humidity of 15 to 90 percent a range in altitude of -170 to 1,700 meters以下為調和後的醫療器材安全及功效綜合符合性評估範本，為便利讀者理解，另提供兩份產品類別導向的範本，一份為血糖機之安全及功效評估範本，一份為非侵入式血壓監測系統 (血壓計) 之安全及功效評估範本。(此二類醫療器材皆為國產醫療器材之大宗，亦大量外銷歐美，具有代表性。) 4 醫療器材採認標準與安全性及功效性評估範本4.1 基本範本一般性原則項次醫療器材安全及功效基本準則GHTF/SG1N41R9:2005衛生署醫療器材採認標準(95.11止)採認標準/相關指引之應用5.1醫療器材在其預期功效與(用途)特定條件下，適當時，須同時考量使用者所具備的技術知識、經驗、教育或訓練狀況，其設計與製造不會影響病患之臨床狀況或安全，影響使用者或其他人士的安全與衛生。其中相關的風險均須與病患效益相衡之後確認可以接受，且應符合高度保障衛生與安全之要求。l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO 14971: Medical devices - Application of risk management to medical devices l IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)l ISO 14155-1 (Clinical investigation of medical devices for human subjects Part 1: General requirements) l ISO 14155-2 (Clinical investigation of medical devices for human subjects Part 2: Clinical investigation plans)l ISO13485:2003 (Medical devices - Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l ISO14971:2000 (Medical devices - Application of risk management to medical devices)l IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)l ISO 14155-1 (Clinical investigation of medical devices for human subjects Part 1: General requirements)l ISO 14155-2 (Clinical investigation of medical devices for human subjects Part 2: Clinical investigation plans)l 請參考其他垂直標準5.2廠商所採用的針對醫療器材之設計與製造解決方案，應符合安全性準則，並納入普遍認定之最佳技術(State-of -the-art)。若有必要降低風險，製造商應管制風險以確保每項危害相關的殘餘風險均在可接受的範圍之內。製造商應依優先次序使用以下原則：l 鑑別已知或可預見的危害、估算預期使用與可預見的誤用相關的風險l 藉由安全地設計與製造，在符合實際的情況下，儘可能消除風險l 藉由採取包括警報在內的適當保護措施，在符合實際的情況下，儘可能消除風險l 將任何殘餘風險告知使用者l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO 14971: Medical devices - Application of risk management to medical devicesl IEC 60601-1-8:2003 (Medical Electrical Equipment - Part 1-8: General Requirements for Safety - Collateral Standard: Alarm Systems Requirements, Tests and Guidelines - General Requirements and Guidelines for Alarm Systems in Medical Equipmentl IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)l ISO13485:2003 (Medical devices - Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)l IEC 60601-1-8:2003 (Medical Electrical Equipment - Part 1-8: General Requirements for Safety - Collateral Standard: Alarm Systems Requirements, Tests and Guidelines - General Requirements and Guidelines for Alarm Systems in Medical Equipment5.3醫療器材應實現製造商所預設的性能，製造商之設計、製造及包裝可使醫療器材得以符合在相關法規系統之下對於醫療器材定義範圍的一個或一個以上的功能l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 510(f) of the Food, Drug and Cosmetic Act-Quality System Regulationl Design Control Guidance for Medical Device Manufacturers5.4醫療器材在製造商所規定的效期之內，或醫療器材在正常使用、且根據製造商規定正確地維護所受到外在壓力的情況下，前述5.1, 5.2與5.3項所規定之特徵與功能不得受到不良影響因而損及病患、使用者或相關人士之健康或安全。l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l 510(f) of the Food, Drug and Cosmetic Act-Quality System Regulation5.5當考慮製造商提供之指引與資訊，醫療器材之設計、製造及包裝須確保，在運送與儲存的條件 (如溫度與溼度)變動時，其指定用途所規定的特徵與性能不應受到不良影響。l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 請參考其他垂直標準l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 510(f) of the Food, Drug and Cosmetic Act-Quality System Regulationl Preproduction Quality Assurance Planning: Recommendations for Medical Device Manufacturers (FDA 90-4236)l 請參考其他垂直標準5.6醫療器材須衡量其預期性能所產生之效益高過任何不良之副作用l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l IEC60812:2006 (Analysis techniques for system reliability Procedure for failure mode and effects analysis (FMEA)產品的設計與製造要求5.7 化學性、物理性及生物特性5.7.1 醫療器材之設計與製造應確保一般要求5.1至5.6項所規定之特徵與性能。尤須注意以下三點：l 所用材料的選擇，尤其是當製造商選用毒性物質及易燃物質(如適用)時l 考量適合於醫療器材的預期用途，其所使用的材料與生物組織、細胞、體液與檢體之間的相容性l 適當時，所選擇的材料應慎重考量其硬度、磨耗與疲勞的強度l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO10993 Biological Evaluationof Medical Device Series: Part 1: Evaluation and testing (ISO 10993-1:2003) Part 5: Tests for in vitro cytotoxicity (ISO 10993-5:1999) Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002/Amd 1:2006)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l FDA blue book memorandum G95-1 (Required Biological Evaluation, Training and Toxicology Profiles for Evaluation of Medical Devices)l Toxicology Risk Assessment Committee #G89-1 (blue book memo)l FDA Immunotoxicity Guidance, May 6, 1999l ISO10993 Biological Evaluationof Medical Device Series: Part 1: Evaluation and testing (ISO 10993-1:2003) Part 2: Animal welfare requirements (ISO 10993-2:2006) Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2003) Part 4: Selection of tests for interactions with blood (ISO 10993-4:2002/Amd 1:2006) Part 5: Tests for in vitro cytotoxicity (ISO 10993-5:1999) Part 6: Tests for local effects after implantation (ISO 10993-6:1994) Part 7: Ethylene oxide sterilization residuals (ISO 10993-7:1995) Part 9: Framework for identification and quantification of potential degradation products (ISO 10993-9:1999) Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002/Amd 1:2006) Part 11: Tests for systemic toxicity (ISO 10993-11:2006) Part 12: Sample preparation and reference materials (ISO 10993-12:2002) Part 13: Identification and quantification of degradation products from polymeric medical devices (ISO 10993-13:1998) Part 14: Identification and quantification of degradation products from ceramics (ISO 10993-14:2001) Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15:2000) Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997) Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002) Part 18: Chemical characterization of materials (ISO 10993-18:2005) Part 19: Physico-chemical, morphological and topographical characterization of materials (ISO 10993-19:2006) Part 20: Principles and methods for immunotoxicology testing of medical devices (ISO 10993-20:2006)l ASTM F895-84(2001)e1, Standard Test Method for Agar Diffusion Cell Culture Screening for Cytotoxicityl ASTM F2148-01, Standard Practice for Evaluation of Delayed Contact Hypersensitivity Using the Murine Local Lymph Node Assay (LLNA)l ASTM F719-81(2002)e1 (Standard Practice for Testing Biomaterials in Rabbits for Primary Skin Irritation)l ASTM F720-81(2002)e1 (Standard Practice for Testing Guinea Pigs for Contact Allergens: Guinea Pig Maximization Test)l ASTM F750-87 (2002)e1 (Standard Practice for Evaluating Material Extracts by Systemic Injection in the Mouse)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 請參考其他垂直標準5.7.2醫療器材之設計、製造與包裝，考慮其預期用途，不受到參與運送、儲存與使用的人員與病患的污染與殘留物所造成之風險。應特別注意暴露的組織與暴露的時間與頻率l 同5.7.1所述l ISO10993-7:1995 (Biological Evaluation of Medical Device Part 7: Ethylene oxide sterilization residuals)l 同5.7.1所述l ISO10993-7:1995 (Biological Evaluation of Medical Device Part 7: Ethylene oxide sterilization residuals)l AAMI / ANSI / ISO 11607:2000 (Packaging for terminally sterilized medical devices)5.7.3 醫療器材之設計與製造，應使其在正常使用或例行程序中接觸到的材料、物質與氣體是安全的。假如醫療器材係用以施以藥品，須與該藥品的規定及限制相容，且其功能也必須根據其預期用途來維持。l 同5.7.1所述l 同5.7.1所述5.7.4若醫療器材包含一單獨使用但為整體的一部份的物質，而物質被相關的法規定義為藥品，且物質之作用於人體為醫療器材的輔助功能者，該物質之安全、品質與可使用性須經過查證以符合醫療器材之預期用途。l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l ISO13485:2003 (Medical devices- Quality management systems - Requirements for regulatory purposes)l ISO/TR 14969:2004 (Medical devices - Quality management systems - Guidance on the application of ISO 13485: 2003)l Design Control Guidance for Medical Device Manufacturersl Do It By Design - An Introduction to Human Factors in Medical Devicesl Human Factors Principles for Medical Device Labelingl Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Managementl5.7.5醫療器材之設計與製造，應儘可能合理地、適當地降低其瀝濾或洩漏出的物質所產生之風險l 中華民國93年11月26日衛署藥字第0930332357號經工字第09304608834號藥物製造工廠設廠標準第四編醫療器材優良製造規範l ISO10993系列標準，除ISO10993-1820 外皆經採認l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 請參考其他垂直標準l ISO10993 Biological Evaluation of Medical Device Series: Part 1: Evaluation and testing Part 14: Identification and quantification of degradation products from ceramics (ISO 10993-14:2001) Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15:2000) Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:1997) Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002) Part 18: Chemical characterization of materials (ISO 10993-18:2005) Part 19: Physico-chemical, morphological and topographical characterization of materials (ISO 10993-19:2006) Part 20: Principles and methods for immunotoxicology testing of medical devices (ISO 10993-20:2006)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 請參考其他垂直標準5.7.6醫療器材之設計與製造，考慮其預期使用的環境特性，應儘可能合理地、適當地降低非預期的進入或來自該器材的物質所產生之風險l ISO14644-1:1999 (Cleanrooms and Associated Conrtolled Environments - Part 1: Classification of Air Cleanliness)l ISO 14644-2:2000 (Cleanrooms and Associated Controlled Environments - Part 2: Specification for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1)l ISO 14644-4:2001 (Cleanrooms and Associated Controlled Environments - Part 4: Design, Construction and Start-up)l ISO 14698-1:2003 (Cleanrooms and Associated Controlled Environments - Biocontamination Control - Part 1: General Principles and Methods)l ISO 14698-2:2003 (Cleanrooms and Associated Controlled Environments - Biocontamination Control - Part 2: Evaluation and Interpretation of Biocontamination Data)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l ISO14644-1:1999 (Cleanrooms and Associated Conrtolled Environments - Part 1: Classification of Air Cleanliness)l ISO 14644-2:2000 (Cleanrooms and Associated Controlled Environments - Part 2: Specification for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1)l ISO 14644-4:2001 (Cleanrooms and Associated Controlled Environments - Part 4: Design, Construction and Start-up)l ISO 14698-1:2003 (Cleanrooms and Associated Controlled Environments - Biocontamination Control - Part 1: General Principles and Methods)l ISO 14698-2:2003 (Cleanrooms and Associated Controlled Environments - Biocontamination Control - Part 2: Evaluation and Interpretation of Biocontamination Data)l ISO14971:2000/Amd.1 2003 (Medical devices - Application of risk management to medical devices)l 請參考其他垂直標準5.8 感染與微生物污染5.8.1 醫療器材製造過程之設計，應儘可能合理地、適當地消除對病患、使用者或其他人員的感染風險。其設計應：l 容易操作，且必要時儘可能合理地、適當地降低從醫療器材洩漏出來及/或使用時暴露於微生物l 避免病患、使用者或其他人員對醫療器材或者檢體之微生物污染l 綜合考慮 5.7.1 及5.7.4項l 綜合考慮 5.7.1 及5.7.4項l ASTM F2065-00e1(Standard Practice for Testing for Alternative Pathway Complement Activation in Serum by Solid Materials)l USP 29-NF21 Biological Testsl AAMI / ANSI / ISO 10993-7:1995 (R) 2001 (Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Sterilization Residuals)5.8.2若醫療器材包含生物來源的物質，應儘可能合理地、適當地降低感染的風險，其措施應藉由選擇適當的來源、捐出者與物質，以及適當時藉由確效過的病毒去活化、保存、檢驗與管制程序ll ASTM F1904-98e1, 2003 (Standard Practice for Testing for Biological Responses to Particles in vivo)l A Proposed Approach to Regulation of Cellular and Tissue-Based Products Docket No. 97N-0068, Feb 28, 19975.8.3在某些法規系統中，包含來自非人體的組織、細胞與物質可能以醫療器材管制。該等來自動物的組織、細胞與物質應受到獸醫的管制與監控確認合於該組織的預期用途。某些國家法規可能會要求製造商及/或法規主管機關包存該動物原料來源之地理資訊。執行加工、保存、檢驗與處理動物來源的組織、細胞與物質應提供最佳安全，尤其是，關於病毒與其他傳染病源之安全性應於製造過程中執行經確效的消除或病毒去活化措施l ISO10993-2, Biological evaluation of medical devices - Part 2: Animal welfare re