目的: 微生物数据偏差（Microbial Data Deviation,MDD）调查在确定药品微生物检验的有效性中发挥了关键作用,但目前国内药品MDD调查的规范有待完善,使制药行业在执行MDD调查中存在一定的困境,本文旨在为药品MDD调查的执行和相关标准提高提供参考依据。方法: 通过调研国内外与药品MDD调查相关的标准指南,如各国药典、GMP指南、美国注射用药协会（Parenteral Drug Association,PDA）技术文件等,从中提炼总结相关的概念、路线、方法;查阅国内外MDD调查相关的案例研究,了解MDD调查发展的历史和现状。结果: 明晰了MDD的概念和特点;MDD调查的流程、根本原因调查等与OOS有许多相近之处,但MDD调查在人员构成等方面更为复杂;建议在MDD调查执行前建立相关标准操作规程,在进行根本原因调查及落实纠正和预防措施的同时,进行微生物风险评估。结论: 目前药品MDD调查已是药品微生物检查中必需的环节,本文可为MDD调查制度建立时的调研提供参考,为药品质量控制及提高提供依据。
Objective: Microbial Data Deviation (MDD) investigation plays a key role in validating the effectiveness of pharmaceutical microbial test. However, the current guidelines on pharmaceutical MDD investigations in China still need to be improved, which poses certain difficulties for the pharmaceutical industry in carrying out MDD investigations. This article aims to provide a reference for the implementation of pharmaceutical MDD investigations and the improvement of relevant standards. Methods: The concept, road map, and methods were summarized by comparing the domestic and international standards related to MDD investigation including national pharmacopeias, GMP guidelines and PDA technical reports, etc. Also, the related study cases were analyzed to reveal the history and current status of MDD investigation. Results: The concept and characteristic of MDD were illustrated. Some technical processes and root cause of MDD investigation were as similar as Out of Specification (OOS) investigation, but the former is more complicated like in stuff composition. It is suggested to construct a serious of standard operating procedures before conducting MDD investigation, and conduct microbial risk assessment when performing root cause investigation and correction and preventive action. Conclusion: Currently, MDD investigation has been a necessary step in pharmaceutical microbial test. This paper provides a reference for investigating and surveying in establishing a MDD investigation system and for the pharmaceutical quality control and improvement.
[1] 国家药品监督管理局食品药品审核查验中心. 药品GMP指南:质量控制实验室与物料系统 [M]. 第2版. 北京:中国医药科技出版社,2023.
[2] Medicines & Healthcare Products Regulatory Agency. Out of Specification & Out of Trend Investigations [EB/OL]. (2017-10)[2024-01-09]. https://www.gov.uk/government/publications/out-of-specification-investigations.
[3] Parenteral Drug Association. Technical Report No. 88, Microbial Data Deviation Investigations in the Pharmaceutical Industry [EB/OL]. (2022-01)[2024-01-09]. https://www.pda.org/bookstore/product-detail/6471-tr-88-microbial-data-deviation.
[4] 中华人民共和国药典: 四部[S]. 2020: 498-503.
[5] 国家市场监督管理总局. 药品生产质量管理规范 [EB/OL]. (2011-01-17)[2024-01-09]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/bgt/art/2023/art_d5e1dbaa8f284277a5f6c3e2fc840d00.html.
[6] European Medicines Agency. Eudralex Volume 4 - EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use [EB/OL]. (2022-01-21) [2024-01-09]. https://health.ec.europa.eu/latest-updates/eudralex-volume-4-eu-guidelines-good-manufacturing-practice-medicinal-products-human-and-veterinary-2022-02-21_en.
[7] Food and Drug Administration. Pharmaceutical Quality Control Labs (7/93), Guide to Inspections of Pharmacal Quality Control Laboratory [EB/OL]. (2014-11-06)[2024-01-09]. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/microbiological-pharmaceutical-quality-control-labs-793.
[8] The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients [EB/OL]. (2000-01-11)[2024-01-09]. https://www.ema.europa.eu/en/ich-q7-good-manufacturing-practice-active-pharmaceutical-ingredients-scientific-guideline.
[9] World Health Organization. Technical Report Series No. 957 Annex1 Good Practices for Pharmaceutical Quality Control [EB/OL]. (2010-09-30)[2024-01-09]. https://www.who.int/publications/m/item/trs957-annex1.
[10] World Health Organization Expert Committee on Specifications for Pharmaceutical Preparations. Technical Report Series No. 908 Annex 4 Good Manufacturing Practices for Pharmaceutical Products: Main Principles [EB/OL]. (2003-06-01)[2024-01-09]. https://www.who.int/publications/i/item/WHO_TRS_908.
[11] World Health Organization. Quality Assurance of Pharmaceuticals: A Compendium of Guidelines and Related Materials: Vol. 2, 2nd Updated Edition: Good Manufacturing Practices and Inspection [EB/OL]. (2007) [2024-01-09]. https://www.who.int/publications/i/item/9789240086081.
[12] 中国食品药品检定研究院. 中国药品检验标准操作规范 [M]. 北京:中国医药科技出版社,2019:744-750.
[13] Food and Drug Administration. Guidance for Industry: Investigating Out-of-specification (OOS) Test Results for Pharmaceutical Production[S]. 2022.
[14] Scott S.The Importance of a Strong SOP System in the QC Microbiology Lab[J]. Journal of GXP Compliance, 14(2): 44.
[15] The United States Pharmacopieial Convention. United States Pharmacopeia <1117> Microbiological Best Laboratory Practices[S]. 2024.
[16] World Health Organization. Technical Report Series No. 961: Annex 2: Good Practices Pharmaceutical Microbiology Laboratories [EB/OL]. (2011-09-30)[2024-01-09]. https://www.who.int/publications/m/item/trs961-annex2.
[17] Food and Drug Administration. Microbiological Pharmaceutical Quality Control Labs (7/93), Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories [EB/OL]. (2014-11-06)[2024-01-09]. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/microbiological-pharmaceutical-quality-control-labs-793.
[18] World Health Organization. Technical Report Series No.1044: Annex 2: WHO Good Manufacturing Practices for Sterile Pharmaceutical Products [EB/OL]. (2022-10-31)[2024-01-09]. https://www.who.int/publications/m/item/trs1044-annex2.
[19] Food and Drug Administration. Microbiological Pharmaceutical Quality Control Labs (7/93), Guide to Inspection of Sterile Drug Substance Manufactures [EB/OL]. (2014-11-13)[2024-01-09]. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/sterile-drug-substance-manufacturers-794#:~:text=GUIDE%20TO%20INSPECTIONS%20OF%20STERILE%20DRUG%20SUBSTANCE%20MANUFACTURERS,IV.%20PROCESSING%20..%205%20V.%20EQUIPMENT%20..%20%E6%9B%B4%E5%A4%9A%E9%A1%B9%E7%9B%AE.
[20] Parenteral Drug Association.Points to Consider No. 1: Aseptic Processing (Revised 2023) [EB/OL].(2023-10)[2024-01-09]. https://www.pda.org/bookstore/product-detail/7418-points-to-consider-asepticprocessing-revised-2023.
[21] European Medicines Agency. Sterilization of the Medicinal Product, Active Substance, Excipient and Primary Container [EB/OL]. (2019-01-10)[2024-01-09]. https://www.ema.europa.eu/en/sterilisation-medicinal-product-active-substance-excipient-primary-container-scientific-guideline.
[22] Food and Drug Administration. Pharmaceutical Microbiology Manual [EB/OL]. (2020) [2024-01-09]. https://www.fda.gov/media/88801/download.
[23] Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme. Aide-Memoire: Inspection of Quality Control Laboratories [EB/OL].(2007-09)[2024-01-09]. https://www.gmp-compliance.org/guidelines/gmp-guideline/pic-s-aide-memoire-on-inspection-of-quality-control-laboratoriespi-023-2-sept-2007.
[24] Personal Care Products Council. Microbiology Guidelines: Investigating Microbial Data Deviations[S]. 2019.
[25] Food and Drug Administration. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing CGMP [EB/OL]. (2004-10)[2024-01-09]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice.
[26] 范一灵,蒋波,房蕊,等. 药品无菌检查中微生物污染的鉴定和污染溯源分析[J]. 药物分析杂志,2011,31(6):1067-1072.
[27] 杨燕,孙梦家,蒋波,等. 药品无菌检查中污染微生物的鉴定与OOS调查分析[J]. 中国医药工业杂志,2016,47(12):1559-1563.
[28] 缪剑虹,孔怡然,刘尧. 医疗器械无菌检查检验结果偏差的调查与分析[J]. 中国医疗器械信息,2023,29(17):38-40,62.
[29] 朱晓燕,陈伟盛,关倩明. 药品无菌检查OOS结果的调查与分析[J]. 中国药事,2017,31(7):750-753.
[30] 陈佩,李松,罗辉艳,等. 实验室微生物数据偏差调查分析的建立及运用[J]. 国际生物制品学杂志,2023,46(4):198-203.
[31] Song M, Li Q, Liu C, et al.A Comprehensive Technology Strategy for Microbial Identification and Contamination Investigation in the Sterile Drug Manufacturing Facility-A Case Study[J]. Front Microbiol, 2024, 15: 1327175.
[32] Muhvich KH. Successful Sterility Test Failure Investigations—A Practical Approach [EB/OL]. (2015-04-06)[2025-01-13]. https://www.americanpharmaceuticalreview.com/Featured-Articles/173160-Successful-Sterility-Test-Failure-Investigations-A-Practical-Approach/.
[33] Sutton S.Laboratory Investigations of Microbiological Data Deviations (MDD)[C]// Laboratory Design: Establishing the Facility and Management Structure (Single User Digital Version), Bethesda: DHI Publishers, 2010: 81-100.
[34] 高海燕,丁恩峰,陈军丽,等. 国际注册中微生物相关MDD调查探讨[J]. 医药工程设计,2011,32(1):29-31.
[35] Sandle T.Sterility Test Failure Investigations[J]. J GXP Compl, 2012, 16(1): 1-8.
[36] 范文平,赵宏大,谢文,等. 药品检验中微生物数据偏差的实验室调查[J]. 中国药师,2015,18(11):1974-1977.
[37] McCullough KZ,Moldenhauer J. Microbial Risk and Investigation [EB/OL]. (2015-04)[2025-01-13]. https://www.pda.org/bookstore/product-detail/4318-microbial-risk-and-investigations.
[38] Moldenhauer J. Conducting Microbial Investigations [EB/OL]. (2015-07-31)[2025-01-13]. https://www.americanpharmaceuticalreview.com/Featured-Articles/177313-Conducting-Microbial-Investigations/.
[39] Peacos P. Essential Points to Consider for Better Microbial Data Deviation Investigations [EB/OL]. (2019-06-03)[2025-01-13]. https://www.pharmaceuticalonline.com/doc/essential-points-to-consider-for-better-microbial-data-deviation-investigations-0001.
[40] ECA Academy. Second Chapter of ECA's Microbiological OOS-OOL Guideline Announced for May [EB/OL]. (2020-02-18)[2025-01-13]. https://www.gmp-compliance.org/gmp-news/second-chapter-of-ecas-microbiologicaloos-ool-guideline-announced-for-may.
[41] Sandle T. Assessing Microbial Contamination: Best Practices for Pharmaceutical Microbial Data Investigations [EB/OL]. (2023-04-01)[2025-01-13]. https://www.americanpharmaceuticalreview.com/Featured-Articles/596293-Assessing-Microbial-Contamination-Best-Practices-for-Pharmaceutical-Microbial-Data-Investigations/.
[42] Scott A. Modern Microbial Methods Supporting a Contamination Control Strategy [EB/OL]. (2025-01-08)[2025-01-13]. https://www.pda.org/pda-letter-portal/home/full-article/modern-microbial-methodssupport-of-a-contamination-control-strategy.
[43] Cundell T. A Review of Out-of-specification Investigations When Using Advanced Microbiological Methods [EB/OL]. (2024-06-01)[2025-01-13]. https://www.americanpharmaceuticalreview.com/Featured-Articles/613504-A-Review-of-Out-of-Specification-Investigations-When-Using-Advanced-Microbiological-Methods/.
[44] 范一灵,秦峰,刘浩,等. WHO药品预认证微生物实验室质量管理的要求与思考[J]. 中国药事,2020,34(4):417-423.
