臺灣博碩士論文加值系統

「ISO 11737-1（2018）」規範是目前全球公認檢測「醫療器材生物負荷量」的標準，此檢測規範也適用於例行微生物監控檢測，如醫材原料、部品、包材、評估清潔過程的效率、整體環境監測、例行成品檢測以做為日常無塵室環境微生物控管的依據指引。本論文主要目標在導入「ISO 11737-1(2018)」規範於醫療器材廠-以S 廠為例，探討未滅菌產品表面微生物的污染來源，及對污染源的有效防範與控管。污染源之實驗設計主要分成兩部份第一部份：人員製程中全部站別均「無戴手套」做為本次研究的實驗組，第二部份全部站別均「戴手套」做為本次研究的對照組，另從成品所檢測出
的微生物選定單一菌落培養純化，並以此菌落往前回推各站別，篩選與成品選定之相同菌落執行菌種鑑定以佐證污染來源。本研究結果顯示在「無戴手套」下執行生產工作，四個站別都是污染源，「有戴手套」可防止手部的微生物沾附在醫材表面上。因此根據本研究結果，如果醫材製造商在製程中能要求操作人員全程戴手套執行工作應可有效防止微生物污染醫材。

"ISO 11737-1 (2018)" is considered to be an important standard specification for the global detection of "biomass in medical equipment". This specification is also applicable to routine microbial monitoring, such as medical materials, parts, and packagings in the production process.. It can also be used as a basis for the efficiency evaluation of the cleaning process, the entire field environmental monitoring and routine finished product testing as a basis for
the daily microbiological control of the clean room environment.
The main goal of this thesis is to introduce the "ISO 11737-1 (2018)" specification to medical device factories-taking S factory as an example, to explore the source of microbial contamination on the surface of unsterilized products, and to effectively prevent and control the source of contamination. The experimental design of the pollution source is mainly divided into two parts. In the process of this research, [1] all stations are "without gloves" as the experimental group; [2] all stations are "with gloves" as the control group. Another research experiment is to select a single colony culture and purification of the microorganisms detected in the finished product, and use the colony to trace back to each station. If the comparison strain is the same as the selected colony of the finished product, then further strain identification is performed to verify the source of contamination. The results of this study show that the four stations in the production process executed under"un-wear gloves" are all sources of pollution. On the contrary, "wear gloves" can prevent microorganisms from the hands to adhere the surface of medical materials. According to the results of this study, if the medical material manufacturer can require all operators to wear gloves during the process, it should prevent microbial contamination of medical materials.

摘要.................................................................i
Abstract............................................................ii
誌謝................................................................iv
目錄................................................................v
表目錄..............................................................viii
圖目錄..............................................................ix
第一章緒論...........................................................1
1.1研究背景..........................................................1
1.2研究動機..........................................................1
1.3研究目的..........................................................2
第二章文獻探討.......................................................3
2.1「ISO11737-1」檢測規範............................................3
2.2台灣醫療器材廠生產環境規範.........................................4
2.3 目前生產製程檢測方法的運用........................................5
2.3.1生產製程監控檢測方法 ............................................6
2.3.2醫療器材ISO11737-1微生物檢測的替代方法...........................6
2.3.3應用ISO11737-1檢測生物膜之存在...................................6
2.3.4目前微生物鑑定方法概況...........................................6
2.4目前微生物相關測試方法之已開發與驗證結果 ............................7
2.4.1依據ISO11737-1檢測規範對醫材生物負荷量培養天數之驗證...............7
2.4.2「ISO 11737-1（2018）手搖、超音波震盪、機械震盪方法查證之結果......8
2.4.3菌種自動檢測系統驗證 ............................................8
2.5目前無塵室微生物污染與控制.........................................9
2.6菌種特性.........................................................10
2.6.1藤黃微球菌(Micrococcus luteus)特性..............................10
2.6.2液化澱粉芽孢桿菌(Bacillus amyloliquefaciens)特性................11
2.7人類手部細菌探討..................................................11
2.8醫療器材熱原之檢測................................................12
第三章材料與方法....................................................13
3.1實驗設計與採樣地點...............................................13
3.2研究架構流程....................................................14
3.3研究方法........................................................15
3.3.1抽樣產品的選擇(實驗設計）抽樣依據...............................15
3.3.2依 ISO11737-1（2018）[1]內容引用於本次檢測方法內................15
3.4 研究中使用之工具................................................15
3.4.1實驗器材及藥品.................................................16
3.4.2採樣及調查方法.................................................17
3.5計算公式.........................................................20
3.6 BIOLOG GEN III自動化微生物鑑定系統操作方法及步驟..................20
第四章實驗結果......................................................22
4.1研究基本資料.....................................................22
4.1.1製程中各站別部品取樣數..........................................22
4.1.2微生物菌落分佈.................................................22
4.1.3「有戴手套」與「無戴手套」菌落分析...............................24
4.1.4細菌類微生物菌落數培養天數與生物膜檢測...........................24
4.1.5 BIOLOG菌種鑑定結果............................................25
第五章討論..........................................................28
5.1「ISO11737-1 2018」規範適用性 ...................................28
5.2工作中無戴套手...................................................28
5.3有戴手套對照組...................................................28
5.4檢測微生物落菌數與醫材表面積比.....................................29
5.5菌種鑑定結果.....................................................29
第六章結論與建議 ...................................................31
參考文獻............................................................33
附錄................................................................38
Extended Abstract..................................................41
1.Introduction.....................................................42
2.Matherials and Methods...........................................43
3.Experiment method................................................43
4.Result...........................................................44
Reference..........................................................45

[1]ISO, 2018,11737-1 Sterilization of health care products —Microbiological
methods —Part 1:Determination of a population of microorganisms on products,
ISO copyright office Published in Switzerland.
[2]TFDA,ISO11737-1,Retrieved from
https://mdlicense.itri.org.tw/MDDB/Recognized/Recognized.aspx
[3]FDA,ISO11737-1 Recognized Consensus Standards, Retrieved from
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/detail.cfm?
standard__identification_no=37512
[4]MDRF USA, List of recognized standards, for 11737-1,Retrived from
http://www.imdrf.org/search.asp?zoom_query=11737-1
[5]ISO,2009,14937 Sterilization of health care products - General requirements
for characterization of a sterilizing agent and the development, validation
and routine control of a sterilization process for medical devices, ISO
copyright office Published in Switzerland.
[6]ISO,2014,11135 Sterilization of health-care products ̶ Ethylene oxide ̶
Requirements for the development, validation and routine control of a
sterilization process for medical devices, ISO copyright office Published in
Switzerland.
[7]ISO,2006,11137 2006: Method 1 Irradiation Validation, ISO copyright office
Published in Switzerland.
[8]ISO,2009,17665-2 Sterilization of health care products —Moist heat —Part 2:
Guidance on the application of ISO 17665-1, ISO copyright office Published in
Switzerland.
[9]ISO,2020,14160 Sterilization of health care products — Liquid chemical
sterilizing agents for single-use medical devices utilizing animal tissues and
their derivatives — Requirements for characterization, development, validation
and routine control of a sterilization process for medical devices, ISO
copyright office Published in Switzerland.
[10]ISO,2018,11737-1 Annex D (INFORMATIVE) Typical assignment of
responsibilities , ISO copyright office Published in Switzerland.
[11]ISO,2016,13485 Medical device -Quality management system-requirements for
regulatory, ISO copyright office Published in Switzerland.
[12]ISO,2015,14644-1 Cleanrooms and associated controlled environments -part 1
classification of air cleanliness by particle concertation Table-ISO Classes
of air cleanliness by particle, ISO copyright office Published in
Switzerland.
[13]行政院衛生署，2006，最終滅菌作業指導手冊，台北，2月。
[14]USP,39,<85>Bacterial endotoxins test, The United States Pharmacopeia
Convention
[15]ISO,2015,14644-1 Cleanrooms and associated controlled environments-part 1
classification of air cleanliness by particle concertation, ISO copyright
office Published in Switzerland.
[16]S Andle,2013, A new standard for bioburden testing, USP chapter in
development. Research gate.
[17]ISO/IEC，2017，17025測試與校正實驗室能力一般要求，ISO版權局在瑞士發行。
[18]衛生福利部，2016，7001非無菌產品試驗，中華藥典第八版，衛生福利部編印。
[19]ISO,2019,11737-2 Sterilization of health care products - Radiation - Part 2:
Establishing the sterilization dose, ISO copyright office Published in
Switzerland.
[20]USP,<1116>Microbial Characterization Identification and Strain Typing, 39,
Pharmacopeia Convention USA.
[21]European Pharmacopoeia,2014,Chapter 5.1.6 Alternative methods for control of
microbiological quality, EDQM – Council of Europe France.
[22]USP,2007,<1223> Validation of Alternative Microbiological Methods Presented
at the 2007 Global Conference on Pharmaceutical Microbiology, pharmacopeia,
Convention USA.
[23]D Carey, JBX Nadell , R Kevin,2009,The sociobiology of biofilms,pp33:206-24,
FEMS Microbiology Reviews USA.
[24]ISO,2018,11737-1 Sterilization of health care products —Microbiological
methods — Part 1:Determination of a population of microorganisms on products
b.2.1.3 Published in Switzerland, ISO copyright office Published in
Switzerland.
[25]USP,<1113>Microbial characterization identification and strain
typing,39,Pharmacopeial Convention USA.
[26]食品藥物管理局TFDA，2011，”微生物鑑定”，第27期，行政院衛生署食品藥物管理局，電子
報。
[27]KA Trabue Bryans,2006,A Comparison of Incubation Periods for Bioburden
Isolates. Biomedical instrumentation & Technology.,pp:76-1,USA.
[28]J Osborne,2001,Assessment of bioburden on human and animal tissues: Part 1-
Results of method development and validation studies, Cell Tissue Bank. USA.
[29]NG GO Sakhno,2016,Microbial Identification Methods in Pharmaceutical
Analysis: Comparison and Evaluation, M J Phar, The Ministry of health of
Russia.
[30]USP,<61>Microbiological examination of nonsterile products: microbial
enumeration tests,39,Pharmacopeial Convention USA.
[31]賴全裕，2011，”個人防護具使用效能評估”，行政院國家科學委員會補助專題研究計畫NSC98-
2221-E-040-003-MY3。
[32]B.Bland,J.Fauver,M.Heintze,C.Torrie,2014, aLIGO Contamination Control Plan
,Massachusetts Institute of Technology ,March.
[33]FDA,2004, Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach
Final Report, Department of Health and Human Services, U.S. Food and Drug
Administration.
[34]FDA,2004,Guidance for Industry, Sterile Drug Products Produced by Aseptic
Processing—Current Good Manufacturing Practice, U.S. Department of Health
and Human Services, Food and Drug Administration.
[35]M Madigan; J E Martinko,2005,Brock Biology of Microorganisms,11th ed.,
Prentice USA.
[36]郭建志等，2014，”液化澱粉芽孢桿菌在作物病害防治的開發與應用”，農業生物資材產業發展
研討會專刊，頁69-86，3月。
[37]J.Fukumoto,1943,”Studies on the production of bacterial amylase. I.
Isolation of bacteria secreting potent amylases and their distribution.”
journal of the Agricultural Chemical Society Japan 19,pp.487-503,July.
[38]王道還，2008，”手上的細菌”，科學發展，432期，頁81，12月。
[39]MH Noah Fierera, L Christian, Lauberb, Rob Knightd.,2008,”The influence of
sex, handedness, and washing on the diversity of hand surface bacteria”, The
National Academy of Sciences,pp.17994–17999,November.
[40]曾嵩斌，2018，”愛家人請洗手”，檢驗醫學與新知，37卷，8期，1月。
[41] 塑膠工業技術發展中心,魏琪珍，醫療器材的生物相容性試驗--熱原試驗(Pyrogen Test）,
取自
https://www.pidc.org.tw/materials.php?id=677
[42]CM OH,2006,”Evaluation of the Phoenix 100 ID/AST System and NID Panel for
Identification of Enterobacteriaceae Vibrionaceae and Commonly Isolated No
enteric Gram-Negative Bacilli”,Journal of clinical microbiology,pp.928-
933,March.
[43]W BA Williams,S Wulff,J Pollitt,2001,”Performance of the BD Phoenix™
Automated Microbiology System in the Identification of Gram-Positive
Bacteria”,101st General Meeting of the American Society for Microbiology,
Poster C-126, Orlando Florida, American.
[44]JL MD Donay, P Fernandes ,C Pregermain ,2004,”Evaluation of the automated
Phoenix system for potential routine use in the clinical microbiology
laboratory”, Journal of clinical microbiology,pp.1542-1546.
[45]SQ CE Van Veen,E Kuijper,2010,”High-throughput identification of bacteria
and yeast by matrix assisted laser desorption ionization-time of flight mass
spectrometry in conventional medical microbiology” laboratories ”,Journal of
Clinical Microbiology, pp.900-907, January.
[46]GF-KP Funke,2004,”Use of the BD Phoenix automated microbiology system for
direct identification and susceptibility testing of gram-negative rods from
positive blood cultures in a three-phase trial.”, Journal of clinical
microbiology ,pp.1466-1470, April.
[47]PC RK Schrec Kenberger, AM Krilcich,2005,”Comparison of the Vitec legacy
Vitek 2 colorimetric and Phoenix systems for identification of fermenting
and nonfermentin, bacteria of clinical origin.”105th General Meeting of the
American Society for Microbiology, Atlanta, GA, USA.
[48]Eigner ,U Wild ,D Bertsch,2005,”Analysis of the comparative workflow and
performance characteristics of the VITEK 2 and Phoenix systems”,Journal of
clinical microbiology ,43(8),pp.3829-3834, August.
[49]Guo L YL, Zhao Q, Ma Y, 2014,”Comparative study of MALDI-TOF MS and VITEK 2
in bacteria identification”, Journal of Thoracic Disease,6(5),pp.534-
538,May.
[50]O Hara ,CM TFamj,1993,”Parallel Comparison of Accuracy of API 20E, Vitek
GNI, Micro Scan Walk/Away Rapid ID, and Becton Dickinson Cobas Micro ID-E/NF
for Identification of Members of the Family Enterobacteriaceae and Common
Gram-Negative, Non-Glucose-Fermenting Bacilli”, Journal of clinical
microbiology,pp.3165-3169,October.
[51]JA SM Odumeru , L Fruhner ,C Larkin ,1999,”Evaluation of accuracy and
repeatability of identification of food-borne pathogens by automated
bacterial identification systems”, Journal of clinical microbiology,pp.944-
949, April.
[52]G MD Funke,C De Bernardis ,A von Graevenitz,1998,”Evaluation of the Vitek 2
system for rapid identification of medically relevant gram-negative rods”,
Journal of clinical microbiology,36(7),pp.1948-1952,July.
[53]Y-W EN Tang, MK Hopkins ,DH Smith,1998,”Comparison of Phenotypic and
Genotypic Techniques for Identification of Unusual Aerobic Pathogenic Gram-
Negative Bacilli”, Journal of clinical microbiology,pp.3674-3679, December.
[54]CA V.W.Sutton,2004,”Microbial Identification in the Pharmaceutical
Industry”, Pharmacopeia forum,30(5),pp.1884-1894,August.
[55]JA BD Kellogg, GS Withers, W Sweimler,2001,”Application of the Sherlock
Mycobacteria Identification System using high-performance liquid
chromatography in a clinical laboratory”, Journal of clinical
microbiology,39(3),pp.964-970,March.
[56]A OA Morey ,BH Himelbloom ,2013,”Identification of Seafood Bacteria from
Cellular Fatty Acid Analysis via the Sherlock® Microbial Identification
System”, Journal of Biology and Life Science,pp.139-153,April.
[57]E BD Carretto , I Couto, D De Vitis,2005,”Identification of coagulase-
negative staphylococci other than Staphylococcus epidermidis by automated
ribotyping”,Clinical microbiology and infection,11(3),pp.177-184,Elsevier
Ltd Netherlands, March,
[58]ISO,1995,11737-1 Sterilization of health care products —Microbiological
methods —Part 1: Determination of a population of microorganisms on
products, ISO copyright office Published in Switzerland.
[59]ISO,2006,11737-1 Sterilization of health care products —Microbiological
methods —Part 1: Determination of a population of microorganisms on
products, ISO copyright office Published in Switzerland.
[60]台美檢驗科技有限公司,為何需要進行菌種鑑定選用方法之剖析,取自
https://www.superlab.com.tw/s155/2017
[61]姚粟等編著，2006，”Biolog微生物自動分析系統-絲狀真菌鑑定操作規程的研究”，食品與發
酵工業，32卷，8期，頁63-67，8月。
[62]K Becker, Eiff von,2001, Staphylococcus, Micrococcus and Other Catalase-
Positive Cocci.In Manual Clinical Microbiology,10th,.,Vo1. 1,.pp.692-
713,Washington,DC ASM press.
[63]P.Rusin,S.Maxwell,C.Gerba,2002,”Comparative surface-to-hand and fingertip-
to-mouth transfer efficiency of gram-positive bacteria, gram- negative
bacteria and phage Transfer of bacteria and phage applied microbiology”,
journal of applied microbiology,93(4),pp.585-592,July.