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发表于 2019-8-1 14:16:40
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tomm 发表于 http://bbs.antpedia.com/thread-325638-1-1.html at 2014-5-2 17:25
进行一下药学考据。。。
1-最早来源
BIOTECHNOLOGY INSPECTION GUIDE (November 1991)
Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?".The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.
这应该是最早来源。
2-Fourman, G.L., and Mullin, Determining Cleaning Validation
Acceptance Limits for Pharmaceutical Manufacturing Operations, Pharm.
Tech., 17(4), 54-60 (1993) - for standard 10 ppm and 1/1000 lowest
theoretical dose calculations based on compounds that are efficacious.
【分析】在1993年的这篇文章，提出了10ppm的限度和1/1000的计算公式基础。
（No more than 10 ppm of any product will apprear in another product. The idea of using a maximum allowable parts-per-millon level has its roots in the regulations that apply to food products.-这是文章中的句子）
很多人因为PDA论坛的影响，认为这是最早来源。但是1991年是在1993年之前，因此还是1991年的指南为最早来源。但是仔细阅读后，会发现他们含义不同。
3-GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993)
V. Establishment of Limits(para 1)
“…Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose,
and organoleptic levels such as no visible residue.”
【分析】FDA指南中的10ppm和第二份资料中含义不同。
4-GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994)
“Specific inspectional coverage for cleaning should include:
3. Analytical Method/Cleaning Limitsart of the answer to the question, "how clean is clean?", is, "how good is your analytical system?". The sensitivity
of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.”
【分析】仔细看，第四份资料和第一份资料基本相同。
5-EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN
QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999)
“Carry-over of product residues should meet defined criteria, for example the most stringent of the following criteria:
no more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,
no more than 10 ppm of any product will appear in another product,
no quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,
for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants
are used for these products.”
【分析】大部分人心中的清洁验证标准终于完全体现出来了！
EU GMP选择含义是根据那篇文献，而不是延续FDA指南的含义。
【综合分析】FDA指南中的10ppm指的是现代分析仪器和分析方法检测限度；其他指南中10ppm指的是产品残留在其他产品中的体现。但是如果简单在验证方案上面写10ppm是不行的，需要论证这个限度。
参见
Selected FDA 483 Observations (May 2000)
Active Pharmaceutical Ingredient Manufacture
“There should be a scientific justification for the specification for residuals stated in the cleaning validation (simply stating <10ppm is not enough!)” |
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