• Still, many confusions on how to select the most suitable, hygienic and cost effective solution然而，在怎么选择最合适、卫生和成本、
效能方面最困惑
• The key is to understand the basic principle
• a permissive range of physical conditions such as理化
条件
– O2 concentration氧浓度 – Temperature温度 – pH
© Alfa Laval
Slide 11
Bacteria and pH 微生物和pH
Growth rate vs. pH for three environmental classes of procaryotes. 原核生物在不同pH条件下的生长速率
Sterile bulk API or BPC
Minimum water type
Suitable noncompendial
PW
WFI
API = Active Pharmaceutical Ingredient活性药用成分（原料药） BPC = Bulk Pharmaceutical Chemical（医药中间体）
© Alfa Laval
Slide 5
USP Specifications定义: PW vs.
WFI
PW (Purified Water) WFI (Water for IFra bibliotekjection)
Water conductivity and < 1,3 μS/cm at 25°C* < 1,3 μS/cm at 25°C*
© Alfa Laval
Slide 4
WFI & PW, in practice WFI和PW的使用
ISPE recommendation ISPE推荐
Bulk API or BPC
Equipment cleaning and rinsing
Non-injectable Injectable dosage form dosage form
This only leaves the Mesophilic bacteria as the main candidate for bacteria that are found in
Bacteria structure 细菌结构
Gram-positive cell wall 葛兰氏阳性菌细胞壁
Gram-negative cell wall 葛兰氏阴性菌
Profiles of the cell envelope the Gram-positive and Gram-negative bacteria. The Gram-positive wall is a uniformly thick layer external to the plasma membrane. It is composed mainly of peptidoglycan (murein). The Gram-negative wall appears thin and multilayered. It consists of a relatively thin peptidoglycan sheet between the plasma membrane and a phospholipid-lipopolysaccharide outer membrane. The space between the inner (plasma) and outer membranes (wherein the peptidoglycan resides) is called the periplasm.
Most common bacteria in pharmaceutical water systems are Gram negative bacteria. Gram negative bacteria do not grow above 60ºC, however, cautions for Gram positive bacteria, which are more heat resistant, should be taken and periodic sanitization and test procedures are recommended.通常在水系统中的微生物多为葛兰氏阴性菌，在高于
60ºC情况下不生长，然而，对于耐热菌，建议要定期清洁处理
Bacteria in pharmaceutical water systems generally range from 0,3 m – 5 m. 水系统中的微生物大小通常在0,3 m – 5 m
© Alfa Laval
Slide 8
Bacteria basics for water systems水系统中的微生物基 本知识
关键是要懂得基本的原理
© Alfa Laval
Slide 2
Water purification & distribution loop纯化和分配
Purification process
Feed water
Reverse Electroosmosis deionisation Tank
Distillation system
© Alfa Laval
Slide 12
Bacteria and Temperature 微生物和温度
Growth rate vs temperature for five environmental classes of procaryotes.
Most procaryotes will grow over a temperature range of about 30 degrees.
质，但过氧化物、次氯酸盐能够降解
Endotoxins are commonly removed by RO, UF, (UV*) and flushing 通常RO
、UF(UV)和冲洗能够去除内毒素
© Alfa Laval
Slide 9
* Argued by some UV manufacturer
•Pharmaceutical Water Systems 制药用水系统
Water storage and distribution system水的贮存和分配系统
• The most common and well known system in the pharmaceutical industry. 是最常规的
CFU=Colony Forming Units
All Pharmaceutical water must also meet the EPA standard for microbiological quality
of potable water
© Alfa Laval
Slide 6
Bacteria basics for water systems水系统中的微生物基 本知识
< 0.25 EU/ml
Production Methods
Obtained by suitable process
Obtained by suitable process and purified by distillation.
*In-line measurement, from equivalent values from USP table
conditions. 制药用水中有机物、矿物质和盐含量非常低，不适宜嗜热 菌的生长
Also the Psychrophilic bacteria, which are mainly found in ice and melt water, are seldom
found in pharmaceutical water systems.很少在制药用水系统中发现主要生长在 冰水中的喜寒性菌
• Aerobic Bacteria 好氧菌
– Gram Negative 葛兰氏阴性菌 – Gram Positive 葛兰氏阳性菌
• Endotoxin 内毒素 • Biofilm 生物膜
© Alfa Laval
Slide 7
Bacteria basics for water systems水系统中的微生物基 本知识
Killed Gram negative bacteria releases endotoxins, which is a lipopolysaccharide molecule that cause fever when injected into the bloodstream. (These substances are termed ”pyrogens” meaning generating heat, fever). Pyrogens have also been linked to more serious reactions when injected into the blood (e.g. lethal septic shock) and are a major concern for every dosage form in contact with the blood stream.杀死
pH
pH 5-7
pH 5-7
Total Organic Carbon < 0.5 ppm (TOC)
< 0.5 ppm
Aerobic Microbial Contamination
< 100 CFU/ ml
< 10 CFU/100 ml (<0.1 CFU/ml)