สํานักงานคณะกรรมการอาหารและยา กระทรวงสาธารณสุข

การประชุม
การพัฒนาหลักเกณฑวิธก
ี ารที่ดีในการผลิตยา (GMP)
ครั้งที่ 2

Pharmaceutical Water
Design & Production

Presented By.
Prapan Ariyamethee (Mr.), Managing Director
Liquid Purification Engineering International co., Ltd. 1

Speaker Biography
Graduated from Chulalongkorn
University in BSc. Chemistry (1972)

Working Experience
„ 14 Years in Sugar Manufacturing & Sugar
Refinery
„ 5 Years in Industrial Chemical & Water
Treatment
„ 12 Years in Application of Membrane for
Industrial use, Design and Installation of
High Purity Water System for
Semiconductor, Pharmaceutical, Power
Plant, Food & Beverage.
2
2

1
 Contents
A) USP 28 Purified Water Standards for Pharmaceuticals.
B) Trend in Pharmaceutical Water Purification Technology.
C) Technology used in Pharmaceutical Water Purification.
D) Development of Treatment Processes for Purified Water.
E) Example; How to purify different feed water analytically, to meet
meet
USP 28 standard.
F) Prevailing problems of existing plant
G) LPE’
LPE’s Gallery
H) Environmental Friendly Process
I) References

3
3

A. USP 28 WFI & Purified Water

Standards for Pharmaceuticals.

4
4

2
 A. USP 28 WFI and Purified Water Standards
USP: United States Pharmacopoeia
Water for Injection

Water for Injection (WFI) is water purified by distillation or by

reverse osmosis that contains no added substances.

Purified Water

– obtained by distillation, ion-exchange treatment,

reverse osmosis, or other suitable process;
– prepared from water complying with the regulations of
the federal Environmental Protection Agency (EPA) with
respect to drinking water;
– contains no added substances.

5
5

A. USP 28 WFI and Purified Water Standards

Component Purified Water Water for

Injection

Conductivity (µS/cm) < 1.3 (25 oC) < 1.3 (25 oC)

Organics (ppb TOC) < 500 < 500

Endotoxin (EU/ml) No specification < 0.25

Bacteria (CFU/100 ml) 10,000 10

(100/ml)

6
6

3
 B. Trend in Pharmaceutical
Water Purification
Technologies

7
7

B. Trend in Pharmaceutical Water

Purification Technologies
1900
Conventional
CATION EXCHANGE ANION EXCHANGE MIXED BED
Pretreatment

Conventional
REVERSE OSMOSIS MIXED BED
Pretreatment

Conventional
REVERSE OSMOSIS EDI
Pretreatment

ULTRAFILTER,
MICROFILTER REVERSE OSMOSIS EDI
2005

8
8

4
 C. Technology used in
Pharmaceutical Water
Production

9
9

C. Technology used in Pharmaceutical Water Production

„ Conventional technology
- Multimedia Filter, Sand Filter, Activated Carbon Filter
- Water Softener, Ion Exchange resin (DMW,MB),
Degasifier
„ Membrane Technology
- Ultrafiltration
- Microfiltration
- Nanofiltration
- Reverse Osmosis
„ Electrodeionization Technology
„ Gas Separation Technology
„ Ozone
„ UV. Sterilizer
10
10

5
 I. Conventional Technology

11
11

C. Technology used in Pharmaceutical Water Production

I. Conventional technology

Multi-Media Filters

Use layers of different filter

media to remove suspended
solids from water. (a typical
multi-media filter has
anthracite in the top layer,
sand in the middle, and garnet
on the bottom);

They are often used in

conjunction with a polymer
feed system and/or coagulant
aid feed system to improve
filtration efficiency.

12
12

6
C. Technology used in Pharmaceutical Water Production
In the multimedia filter;
•largest media is the least dense and at the top of the bed,
•smallest particles are heaviest and are at the bottom of the vessel.

13
13

C. Technology used in Pharmaceutical Water Production

I. Conventional Technology

Activated Carbon
Filter Unit

14
14

7
C. Technology used in Pharmaceutical Water Production
I. Conventional Technology

Softener, Cation,
Anion Unit

15
15

C. Technology used in Pharmaceutical Water Production

I. Conventional Technology

Forced Draft
Decarbonator

16
16

8
C. Technology used in Pharmaceutical Water Production

I. Conventional Technology

Mixed-Bed Unit

17
17

II. Membrane Technology

18
18

9
 C. Technology used in Pharmaceutical Water Production

Membrane Process Characteristics

Monovalent Multivalent Oil & Colloids
Water Surfactants Grease material
Metals Metals
Microfiltration

Oil & Colloids

Monovalent Multivalent
Surfactants Grease material
Water Metals Metals
Ultrafiltration

Oil & Colloids

Monovalent Multivalent Surfactants material
Metals Grease
Water Metals
Nanofiltration

Oil & Colloids

Monovalent Multivalent Surfactants Grease material
Water Metals Metals
Reverse Osmosis

19
19

THE FILTRATION SPECTRUM

0.001 0.01 0.1 1.0 10 100 1000

µm

4 5 6 7
10 100 1000 10 10 10 10
A

MOLECULAR
100 200 5,000 20,000 100,000 500,000
WEIGHT

Aqueous salts Carbon black Paint pigment

Pyrogens Yeast cells Beach sand

RELATIVE
SIZE OF
COMMON Metal ions Virus Bacteria
MATERIAL
Colloidal silica Pollens
Sugars
Albumin protein Milled flour

FILTRATION NF Microfiltration
TECHNO-
LOGY RO Ultrafiltration Particle filtration
20
20

10
C. Technology used in Pharmaceutical Water Production

Dead End/Static Filtration Crossflow Filtration

Filter cake

Concentrate

Membrane

Filtrate Filtrate

Time Time
Specific filtrate flux
21
21 Thickness of filter cake/of the dynamic layer

C. Technology used in Pharmaceutical Water Production

Membrane Configuration
Plate & Frame – Flat Sheet

Tubular

Hollow Fiber

Spiral
22
22

11
 III. Electrodeionization Technology

23
23

Exploded View (Resin Not Shown)

III. Electrodeionization Technology
Product
Reject compartment
compartment
Electrode block

Anion membrane
Cation
membrane
Cathode

Endplate 24
24

12
 Ion Removal in a LX™ Module

III. Electrodeionization Technology

25
25

C. Technology used in Pharmaceutical Water Production

Salt Removal Using Ion Exchange Membranes

III. Electrodeionization Technology

26
26

13
C. Technology used in Pharmaceutical Water Production

Ionpure LX System Simplicity

DC Power Supply
and Electrical Controls

FEED PRODUCT

CONCENTRATE

IP-LX Module
III. Electrodeionization Technology
27
27

IV. Gas Separation technology

28
28

14
C. Technology used in Pharmaceutical Water Production
IV. Gas Separation technology

Extra-
Extra-Flow Membrane Contactor

• Patented Design
• FDA Compliant
(With Appropriate O-Rings)
29
29

C. Technology used in Pharmaceutical Water Production

IV. Gas Separation technology

Principles of Gas Transfer

χ O2
„ Gasses in the atmosphere dissolve
into water until equilibrium is
reached
Equilibrium between the liquid and
LIQUID

„
gas phase is offset when a vacuum
and/or source of strip gas is yO
applied 2

„ This creates a driving force to Vacuum

move gasses from the liquid phase and/or
into the gas phase Sweep
Gas
Liquid/Gas contact
area at the pore
30
30

15
C. Technology used in Pharmaceutical Water Production

IV. Gas Separation technology

SEM of Celgard® Microporous
Polypropylene Hollow Fiber Membrane

Fiber Types:
200-220 µm
All variants are nonselective but
each has attributes that makes it
300 µm
more suited for certain applications
- X40: O2 Removal
- X50: CO2 Removal
- Polyolefin: Low
Surface Tension Fluids

0.03 µm Average Pore

31
31

C. Technology used in Pharmaceutical Water Production

IV. Gas Separation technology

Available Membrane Contactor Products Summary

Applications: Debubbling

Product Flow Range (one device)

MiniModule® 1 x 5.5 Up to 500 ml/min
MiniModule® 1.25 x 5 Up to 2500 ml/min

Applications: Gas Transfer

(O2,CO2,N2,VOC removal, and O2,CO2,N2, H absorption)

Product Flow Range (one device)

Liqui-Cel® Extra-Flow 2.5 x 8 0.5 – 3 gpm (0.1 – 0.7 m3/hr)
Liqui-Cel® Extra-Flow 4 x 13 5 – 15 gpm (1.1 – 3.4 m3/hr)
Liqui-Cel® Extra-Flow 4 x 28 5 – 30 gpm (1.1 – 6.8 m3/hr)
Liqui-Cel® NB™ and Extra-flow 6 x 28 5 – 50 gpm (1.1 – 11.4 m3/hr)
Also in INDUSTRIAL version 44 – 210 gpm (10 – 48 m3/hr)
Liqui-Cel® Extra-Flow 14 x 28 70 – 400 gpm (16-90.8 m3/hr)

* X50 in our high-purity 10-inch contactor is currently rated to 210 gpm in one device 32
32

16
 V. Ozone Technology

33
33

C. Technology used in Pharmaceutical Water Production

V. Ozone Technology

Oxygen Ozone
(O2) (O3)

OO1
O3
Ultraviolet Light or O2 1

Corona Discharge
O3
O2 O1
Some O2 and reassembles
molecules with other O2 molecules
break apart to form ozone

In nature, Ozone is created/ formed when the oxygen molecules in the air are struck by
either ultra-violet rays from the sun or by an electric charge, such as lightning.

Some of the oxygen molecules (O2) split up by these forces into single oxygen atoms (O1)
which then combine with other O2 molecules to form ozone (O3).

34
34

17
C. Technology used in Pharmaceutical Water Production
V. Ozone Technology

Artificially, ozone molecules are produced in two ways :

1. By forcing oxygen or ambient air to pass through an ultraviolet light

source matching the (ozone producing) wavelength of the sun’s rays
(185 nanometers).

2. By sending a lightning-like spark (a “corona discharge”) through an

oxygen or dry air flow.

Ozone is highly unstable, it reverts back to its original state as diatomic

oxygen (O2) after coming in contact with the microorganisms (this impact
kills the microorganisms)

35
35

VI. UV. Sterilizer

36
36

18
 C. Technology used in Pharmaceutical Water Production
VI. UV. Sterilizer

UV energy is found in
the electromagnetic
spectrum between
visible light and x-rays
and can be described
best as an ‘invisible
radiation’

37
37

C. Technology used in Pharmaceutical Water Production

VI. UV. Sterilizer

Disinfection
All living organisms contain DNA
(deoxyribonucleic acid). DNA provides the
mechanism for all functions needed to
sustain life.
Disinfection systems emit UV light that
penetrates the outer cell membrane of
microorganisms, which then passes through
the cell body, reaching the DNA and
altering the genetic material.
Disinfection system destroys the
microorganisms in a non-chemical manner
and disables their reproductive system.
38
38

19
C. Technology used in Pharmaceutical Water Production
VI. UV. Sterilizer

Example; Ultraviolet Doses Required for 99.9% Inactivation of

(mW-s/cm2)*
Various Microbes (mW-

Virus UV Dose Virus UV Dose

Adenovirus Type 3 7,400 Poliovirus 22,500

Bacteriophage 10,800 Rotavirus 28,500

Coxsackie A 9,500 Tobacco Mosaic virus 720,000

Hepatitis A 21,900 Influenza virus 10,800

39
39

C. Technology used in Pharmaceutical Water Production

VI. UV. Sterilizer

Example; Ultraviolet Doses Required for 99.9% Inactivation

(mW-s/cm2)*
of Various Microbes (mW-

Bacteria UV Dose Bacteria UV Dose

Bacillus anthracis (veg.) 13,500 Corynebacterium diptheriae 10,200

Bacillus anthracis (spores) 163,500 Escherichia Coli. 9,600

Bacillus megatherium (veg.) 3,600 Leptospira 10,200

Bacillus megatherium (spore) 8,100 Micrococcus candidus 18,000

Bacillus subtilis ( veg.) 10,000 Micrococcus radiodurans 61,500

Bacillus subtilis (spore) 56,000 Clostridium tetani (spores) 36,000

40
40

20
C. Technology used in Pharmaceutical Water Production
VI. UV. Sterilizer

Example; Ultraviolet Doses Required for 99.9% Inactivation

of Various Microbes (mW-s/cm2)*

Bacteria UV Dose Bacteria UV Dose

Micrococcus sphaeroides 30,000 Pseudomonas fluorescens 10,500

Mycobacterium tuberculosis 17,400 Salmonella enteritidis 12,000
Neisseria catarhhalis 13,200 Salmonella paratyphi 9,600

Phytomonas tumefaciens 13,200 Salmonella typhi 6,300

Proteus vulgaris 7,800 Salmonella typhimurium 24,000

Pseudomonas aeruginosa 16,500 Sarcina lutea 59,100

41
41

D. Development of Water
Treatment Processes for
Purified Water

42
42

21
 D. Development of Water Treatment Processes for Purified Water

System 1. Deionization
System 2. Deionization with hot distribution
System 3. Deionization with ozonated storage
System 4. Deionized with Ultrafiltration
System 5. Reverse Osmosis
System 6. Reverse Osmosis with hot distribution
System 7. Reverse Osmosis with ozonated storage
System 8. Reverse Osmosis with MEMBREL ozone
System 9. Double Pass Reverse Osmosis with ozonated storage
System 10. RO-
RO-EDI with ozonated storage
System 11. UF/MF-
UF/MF-RO-
RO-EDI with ozonated storage

43
43

D. Development of Water Treatment Processes for Purified Water

TEMP DUMP

FEED
WATER
CARTRIDGE
FILTER
TWO BED
MIXED BED
DEIONIZATION
MMF CF
UV

POINT
OF
USE

CARTRIDGE CARTRIDGE
FILTER FILTER

SYSTEM 1 : CONVENTIONAL DEIONIZATION

UV

44
44

22
 D. Development of Water Treatment Processes for Purified Water

TEMP DUMP
SYSTEM 2 : DEIONIZATION WITH
RECIRCULATION
HOT DISTRIBUTION

FEED
WATER
CARTRIDGE
FILTER
TWO BED
MIXED BED
DEIONIZATION
MMF CF
UV

POINT VENT
CARTRIDGE CARTRIDGE
OF FILTER HOT
STORAGE FILTER FILTER
USE TANK

STEAM
UV

45
45

D. Development of Water Treatment Processes for Purified Water

TEMP DUMP SYSTEM 3 : DEIONIZATION WITH

RECIRCULATION OZONATED STORAGE

FEED
WATER

CARTRIDGE
FILTER
TWO BED
MIXED BED
DEIONIZATION
MMF CF
UV

OZONE
DECOMPOSER

POINT CARTRIDGE CARTRIDGE

OF VENT STORAGE FILTER FILTER
USE FILTER TANK

UV
OZONE
SYSTEM

UV 46
46

23
 D. Development of Water Treatment Processes for Purified Water
TEMP DUMP

RECIRCULATION

FEED
WATER
CARTRIDGE
FILTER
TWO BED
MIXED BED
DEIONIZATION
MMF CF
UV

POINT
OF
USE

CARTRIDGE
ULTRAFILTER FILTER

UV

SYSTEM 4 : DEIONIZATION WITH ULTRAFILTRATION

47
47

D. Development of Water Treatment Processes for Purified Water

TEMP DUMP SYSTEM 5 : REVERSE OSMOSIS

RECIRCULATION

REVERSE OSMOSIS
(RO)

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

NITROGEN
BLANKET
STORAGE POINT
TANK OF
USE

CARTRIDGE CARTRIDGE
FILTER FILTER
MIXED BED

UV
48
48

24
 D. Development of Water Treatment Processes for Purified Water

SYSTEM 6 : REVERSE OSMOSIS

TEMP DUMP
WITH HOT DISTRIBUTION
RECIRCULATION

REVERSE OSMOSIS
(RO)

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

NITROGEN
BLANKET POINT
HOT
STORAGE
TANK
STORAGE VENT OF
TANK FILTER USE

STEAM

CARTRIDGE CARTRIDGE
FILTER FILTER
MIXED BED

UV
49
49

D. Development of Water Treatment Processes for Purified Water

SYSTEM 7 : REVERSE OSMOSIS
TEMP DUMP
WITH OZONATED STORAGE
RECIRCULATION

REVERSE OSMOSIS
(RO)

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

OZONE
DECOMPOSER

POINT
STORAGE VENT
TANK FILTER
OF
USE

CARTRIDGE CARTRIDGE COVENTIONAL

FILTER FILTER OZONE
MIXED BED SYSTEM

UV
50
50

25
 D. Development of Water Treatment Processes for Purified Water

SYSTEM 8 : REVERSE OSMOSIS

TEMP DUMP
WITH OZONE
RECIRCULATION

REVERSE OSMOSIS
(RO)

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

MEMBREL
OZONE
N2

STORAGE POINT
TANK OF
USE

CARTRIDGE CARTRIDGE
FILTER FILTER
MIXED BED

UV
51
51

D. Development of Water Treatment Processes for Purified Water

TEMP DUMP

RECIRCULATION

DOUBLE
PASS RO

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

OZONE
DECOMPOSER

POINT
STORAGE
VENT TANK
OF
FILTER USE

SYSTEM 9 : DOUBLE PASS

OZONE
CARTRIDGE
FILTER
REVERSE OSMOSIS

UV

52
52

26
 D. Development of Water Treatment Processes for Purified Water

TEMP DUMP
SYSTEM 10 : REVERSE OSMOSIS + EDI
RECIRCULATION

RO
(ONE/TWO PASS)

FEED
WATER
CARTRIDGE CARTRIDGE
FILTER FILTER

MMF CF
UV

OZONE
DECOMPOSER

STORAGE POINT
VENT TANK OF
FILTER USE

CARTRIDGE
OZONE FILTER
EDI

UV
53
53

D. Development of Water Treatment Processes for Purified Water

SYSTEM 11 :UF/MF + REVERSE

TEMP DUMP
OSMOSIS + EDI
RECIRCULATION

RO
(ONE/TWO PASS)

FEED
WATER

CARTRIDGE
FILTER
PRE-
FILTER UF/MF

OZONE
DECOMPOSER

STORAGE POINT
VENT TANK OF
FILTER
USE

CARTRIDGE
OZONE FILTER
EDI

UV
54
54

27
 E. Example
How to purify analytically,
different feed water to meet
USP 28 standard.

55
55

E. How to purify analytically, different feed water to meet USP 28 standard.

Various Inlet Water

Clarified Deep well City water
Parameter Unit water
Bangpakong Samutsakorn Bangkok
Turbidity NTU 2.3 1.5 0.7
pH - 7.37 7.489 7.473
Conductivity µS/cm 956 1,011 239
TDS mg/l 669 758 168
M- Alkalinity mg/l as CaCO3 80.0 273.34 54.18
Total Hardness mg/l as CaCO3 115.0 358.55 80.80
Ca-Hardness mg/l as CaCO3 59.4 209.10 51.0
Chloride mg/l as Cl- 189.41 150.82 13.06
Iron mg/l as Fe 0.08 0.11 < 0.2
Sulfate mg/l as SO4-2 74.53 37 <5
Phosphate mg/l as PO4-3 0.41 < 0.05 -
Silica mg/l as SiO2 15.35 22.6 12

56
56

28
E. How to purify analytically, different feed water to meet USP 28 standard.

Raw water analysis USP 28

DW SF City PW WFI
Cond. 1.3 1.3
Cond. 900 1,000 240 TOC < 500 < 500
TDS 670 750 170
TH 120 350 80 Bacteria 10,000 10
Cl 200 150 13 Endotoxin - < 0.25
TOC ~2,000 ~9000 ~5000

57
57

E. How to purify analytically, different feed water to meet USP 28 standard.

Water Treatment System

Consisting of 3 parts

1) Pre-
Pre-treatment part

2) Make-
Make-up part

3) Polishing part

58
58

29
E. How to purify analytically, different feed water to meet USP 28 standard.
Pre-treatment part
SURFACE
WATER
MF/UF Make-up part

Al2(SO4)14.3H2O Polishing part

Cl2
Na2CO3/Ca(OH)2 FLOCCULANT
antiscale
(Cationic Polymer)

SURFACE
WATER

WELL CLARIFIER

WATER MULTIMEDIA CARBON 5µ FILTER RO EDI

FILTER FILTER

WELL WATER
(WITH HIGH Fe)
POINT
STORAGE
VENT TANK
OF
FILTER USE
DEIRON
FILTER

CARTRIDGE
OZONE FILTER

UV
59
59

F. Existing problems of the plant

60
60

30
 F. Existing problems of plant

„ Too small space and poor environmental.

„ Wrong location & Water treatment plant.
„ Limited budget.
„ Employment of wrong technology.
„ Lack of technical and responsible person (supplier/customer).
„ Misuse of materials.
„ Improper material management of acid, alkaline solution, etc.
„ Selection of wrong membrane material
„ Outdated piping technology

61
61

G. LPE’s Gallery

62
62

31
 Membrane type: Ultrafiltration / Ion Exchange Resin
Application: Final Filtration

Hot water sanitizer-

sanitizer- Column

63
63

Membrane Type: RO
Application: Purified Water
Hot water sanitizer-
sanitizer- RO

64
64

32
 Membrane Type: RO
Application: Purified Water

capacity 10 m3/hr

65
65

Membrane Type: RO-

RO-EDI
Application: Purified Water

3-6 m3/hr
Capacity 3-

66
66

33
Membrane Type: RO-
RO-EDI
Application : Purified Water

Capacity 0.5 m3/hr

67
67

Membrane type: Ultrafiltration

Application: Final Filtration

Capacity
2,400-
2,400-5,000 ltr/hr

68
68

34
 H. Environmental Friendly Process

69
69

H. Environmental Friendly Process

Feed Water
Turbidity < 0.5 NTU
SDI < 3

STORAGE STORAGE
TANK TANK

Ro Pre-treatment MF water tank Carbon Double pass RO RO water tank

With Microfiltration filter

POINT N2
OF
USE STORAGE
TANK

CO2 < 1 ppm

ULTRAFILTER FILTER
DI. water tank 1 micron
EDI Degas
safety filter
UV Membrane

70
70

35
 I. References
1. Theodore H. Meltzer. “Pharmaceutical Water Systems” Tall Oaks Publishing. Inc.
2. Glegg Industrial Water “GRD2000”
GRD2000” Reference design.
3. Aquafine Corporation 29010 Avenue Paine, Valencia, CA. USA.
4. Celgard,
Celgard, LLC., 13800 South Lakes Drive, Charlotte, NC. USA.
5. IonPure Technologies, Inc. 10 Technology Drive. Lowell, MA. USA.
6. Koch Membrane System, Inc. 850 Main Street, Wilmington, MA.
MA. USA.
USA.

71
71

72
72

36