Pharmaceutical Water System Design
and Regulatory Requirements
AIChE New Jersey Section
November 9, 2005
Gary V. Zoccolante
Pharmaceutical Technical Director
US Filter
1
Basic Regulatory Background
USP
United States Pharmacopoeia Convention
USP 27
Private
USP
Not for profit
Sets therapeutic
drug standards
3
FDA
Food and Drug Administration Legally enforces drug standards
Efficacy
Safety
FDA
Purity
Strength
4
FDA/USP
FDA cant set drug
standards but enforces
them
FDA/USP
USP sets drug standards, but
cant enforce them
FDA must enforce
USP monographs
USP 27 Pharmaceutical Water
Compendial Types
Bulk forms
1.
Purified Water (PW)
Water for Injection (WFI)
Water for Hemodialysis
Packaged Forms
2.
Bacteriostatic WFI
Sterile Water for Inhalation
Sterile Water for Injection
Sterile Water for Irrigation
Sterile Purified Water
USP Purified Water
1.
Produced by Suitable Process
2.
Prepared from water meeting EPA NPDWR
or comparable regulations
3.
Contains no added substance
4.
Not for use in parenteral or sterile dosage
forms
7
USP 27 Purified Water Quality
Requirements
Conductivity: 3 stage measurement procedure
1.
No temperature compensation allowed
Stage 1 online or lab test
Stage 2 and 3 lab tests
2.
Total Organic Carbon: 500 ppb limit response
3.
Microbial Action Limit: 100 cfu / ml maximum - may
be lower for specific process and product
applications
8
Current USP <645> Stage 1 and EP WFI Conductivity
Limits
Uncompensated Conductivity(S/cm)
10.0
9.0
Cl Model
8.0
NH3 Model
7.0
USP <645> Stage 1 Limit
6.0
5.0
4.0
3.0
2.9 3.1
2.7
2.7
2.7
2.7
2.0
2.5
2.2 2.4
2.1
1.7 1.8 1.9
1.0
1.5
1.4
1.1 1.3
1.0
0.9
0.0 0.6 0.8
10
20
30
40
50
60
Temperature (C)
70
80
90
100
Current <645> Stage 3 and EP Conductivity Limits at
25C
Uncompensated Conductivity ( S/cm)
10.0
9.0
Cl model
NH3 model
USP <645> Stage 3 limit
EP WFI limit at 20C
EP PW limit at 20C
8.0
7.0
6.0
5.0
4.0 4.7
4.1
3.0
4.6
3.6
2.0
1.0
3.3
3.8
3.1
3.0 2.8
2.6 2.5 2.4 2.4 2.4 2.4 2.5 2.4 2.3
2.6
2.2 2.1
0.0
5.0
5.2
5.4
5.6
5.8
6.0
6.2
6.4
6.6
6.8
pH
10
7.0
EP Conductivity Limits
effective July 1, 2004
Uncompensated Conductivity
(
S/cm)
10.0
10.2
9.7 9.7
9.0
9.7
9.1
8.0
8.1
7.0
7.1
6.0
6.5
5.0
5.1
4.0
5.4
4.3
3.0
Proposed EP Purified Water
Limits
Proposed EP WFI Limits
3.6
2.0 2.4
1.0
1.3 1.4 1.4
1.1
1.0
0.9
0.0 0.6 0.8
10
20
30
2.9 3.1
2.7
2.7
2.7
2.7
2.5
2.2 2.4
2.1
1.7 1.8 1.9
40
50
60
Temperature (C)
70
80
90
11
100
Water for Injection Monograph
Requirements
1.
Meets all requirements for Purified Water
2.
Produced by distillation or purification
process proven to be equal to or superior to
distillation
3.
Passes Bacterial Endotoxin test - not more
than 0.25 EU/ml
4.
Microbial Action Limit: 10 cfu / 100 ml maximum may be lower for specific process and product
applications
12
EP Monograph Specifications
Effective July 1, 1999
Purified Water
Conductivity..See table
Conductivity Stage 1,2,3 N/A
TOC < 500 ppb or oxidizable
substance test
13
EP Monograph Specifications
Purified Water
Nitrates - current test
Heavy metals - current test
Aluminum - current test (for bulk water for
dialysis only)
Endotoxin <0.25 IU/ml (for bulk water for
dialysis only)
Bacteria (guideline) <100 cfu/ml
14
EP Monograph Specifications
Water for Injections
Method of production - distillation
Conductivity <1.1 uS/cm at 200C
Conductivity Stage 1,2,3 N/A
TOC <500 ppb
Endotoxin <0.25 IU/ml
Bacteria (guideline) <10 cfu/100 ml using
minimum 200 ml sample volume
15
Determining Water Quality
Requirements
16
Specifying Water Quality
1.
Must establish logic for quality based upon
end product
2.
Purified Water minimum quality for oral
dosage ingredient
17
Specifying Water Quality
3.
WFI minimum quality for parenteral drug
ingredient
4.
Consistent with final product requirements
5.
May need to exceed compendial requirements
(PW or WFI)
18
Specifying Water Quality
6.
WFI expected to be used for some
ophthalmic and inhalation products
7.
API water quality determined by
manufacturer
Drinking water may be acceptable
Chemical, microbial, or endotoxin specs may be
established
WFI quality may be required
19
Specifying Water Quality
Pharmaceutical water categories
Ingredient in dosage form
Ingredient in Active Pharmaceutical Ingredient
(API) or Bulk Pharmaceutical Chemical (BPC)
Equipment cleaning or rinsing
20
Select Water Designation
Manufacturing Water
used for:
Parenteral
Production
Non-parenteral
Dosage Forms
WFI
USP Purified
Select Water Designation
Cleaning Water
used for:
Final Rinse?
NO
Suitable
non-compendial
YES
Use same quality water
as Product Manufacturing
Select Water Designation
API / BPC
Manufacturing Water
used for:
NO
Sterile API
Non-Sterile API
Downstream
Processing?
Parenteral
Product?
YES
NO
YES
Endotoxin removed in later steps
WFI
USP Purified
equivalent quality
Suitable
non-compendial
WFI Equivalent
Quality
cGMP Requirements
24
Good Manufacturing Practices
The law enables the FDA to enforce
strict adherence to the cGMPs
1.
The FDA initiates action through the
federal judicial system
Penalties are imposed by the federal
court system
25
Good Manufacturing Practices
FDA finds manufacturing or control
procedures not to cGMPs
1.
may deem products adulterated
may impose sanctions
with or without contaminated products
26
21 CFR Part 210
1.
States applicability and definition for cGMP
regulations
2.
No direct reference to pharmaceutical
water systems
3.
A component [is] any ingredient intended
for use in the manufacture of a drug
product, including those that may not
appear in such drug product - 21 CFR 210
27
21 CFR Part 210 Interpretation
1.
Pharmaceutical waters used in the
manufacture of drugs or drug products
are subject to the regulations of the
cGMPs whether or not the water remains
in the final product
28
21 CFR Part 211
General regulations regarding
manufacturing of finished
pharmaceuticals
1.
No direct water system requirements
No water quality requirements
Few water system design sections
29
21 CFR 211.65a
Surfaces that contact components, inprocess materials, or drug products shall
not be reactive, additive, or absorptive so
as to alter the safety, identity, strength,
quality, or purity of the drug product
30
21 CFR 211.65a Interpretation
1.
Opens all process water contact
surfaces to FDA scrutiny
2.
Implies use of inert materials for
product water handling
3.
Manufacturer must prove suitability
of system components and
materials
31
21 CFR 211.67a
Equipment shall be cleaned, maintained,
and sanitized at appropriate intervals to
prevent malfunctions or contamination that
would alter the safety, identity, strength,
quality, or purity of the drug product
beyond the official or other established
requirement
32
21 CFR 211.67a Interpretation
Routine maintenance plans
required for all equipment
1.
Individual unit monitoring required
Sanitization frequency dependent on
product water quality requirements
and system design
33
21 CFR 211.67a Interpretation
1.
Opens equipment rinse water to review
2.
Rinse water should be free of
objectionable contaminants
3.
Final rinse water shall be of equal quality
to manufacturing water
4.
Final rinse for parenteral production
could be interpreted to be:
WFI
WFI equivalent (e.g. by ultrafiltration)
34
21 CFR 212 - GMPs for Large Volume
Parenterals (GMP/LVP)
1.
Proposed in 1976
2.
Abandoned in 1994
3.
Specific requirements for parenteral
water systems
35
21 CFR 212 - GMPs for Large Volume
Parenterals (GMP/LVP)
1.
No legal standing.however
2.
Many concepts now common
industry practice and cGMP
36
21 CFR 212 Impact
Minimal dead legs
2. No point-of-use filters in WFI loop
3. Most WFI distribution systems 316 SS
4. Double tube sheet heat exchangers or differential pressure
monitoring
5. Tank vent filters
6. Sloped piping
7. Pump flush seals
8. 24 hour dump rule
9. Final rinse water WFI quality
10. No volatile steam additives
1.
37
Purified Water System Design
38
Water
H2O
Anything in water that is not
H+ or OHis an impurity.
The objective of water treatment is
removal of impurities from the water.
39
Impurities
1.
Ionic
2.
Organic
3.
Particulate
4.
Microbiological
5.
Gases
40
Processes for Suspended Solids
Removal
1.
2.
3.
4.
5.
6.
Multi media filter
Disposable cartridge filter
Ultrafilter
Microfilter
Reverse osmosis
Submicron filter
41
Processes for Conductivity Reduction
1.
Reverse Osmosis
2.
Ion Exchange
regenerated on-site
regenerated off-site
3.
Continuous Electrodeionization
4.
Distillation
42
Processes for TOC Reduction
1.
Activated carbon
2.
Organic scavenger resin
3.
Reverse Osmosis
4.
Ultrafiltration
5.
Ultraviolet oxidation (185 nm or medium
pressure)
6.
Distillation
7.
Ozone
43
Processes for Microbial Control
1.
2.
3.
4.
5.
6.
7.
8.
Residual disinfectant
Ultraviolet light
Reverse osmosis
Distillation
Ultrafiltration
Submicron filtration
Ozone
Continuous heat
44
Pure Water System Configuration
Feed
Water
Pretreatment
Primary
Treatment
Optional
Polishing
45
System 1: Reverse Osmosis /
Continuous Deionization (RO/CEDI)
Multi-media
Filter
Dual Softeners
Break Tank
Heat
Exchanger
Hot Water
Sanitizable
Activated Carbon
Unit
to storage and
5 Micron
Prefilter
254 nm UV
Hot Water
CEDI Unit
Sanitizable
Reverse Osmosis
Unit
distribution
254 nm UV
0.1 micron
Final Filter
46
System 2: Two Pass Reverse Osmosis / NonRegenerable Deionization (TPRO/NRDI)
Multi-media
Filter
Dual Softeners
Break Tank
Heat
Exchanger
Hot Water
Sanitizable
Activated Carbon
Unit
254 nm UV
5 Micron
Hot Water
RO Prefilter Sanitizable Two
Pass
Reverse
OsmosisUnit
Optional pH
Adjustment
NonRegenerable
Mixed Bed
Deionization
0.1 micron
254 nm Final Filter
UV
to storage and
distribution
47
RO / CDI / Continuous Hot RO or UF
Multi-media
Filter
Dual Softeners
Break Tank
Heat
Exchanger
Hot Water
Sanitizable
Activated Carbon
Unit
CEDI Unit
5 Micron
Prefilter
254 nm UV
Hot Water
Sanitizable
Reverse Osmosis
Unit
Purified Water
Storage Tank
WFI to
Storage
Heat
Continuous Hot RO or UF
Exchanger
Unit
48
System 3: Vapor Compression
Distillation
Dual Softeners
Heat
Exchanger
Hot Water Sanitizable
Activated Carbon
Unit
5 Micron
Prefilter
Optional Hot Water
Sanitizable
Reverse Osmosis
Unit
Vapor
Compression
Still
to
storage
and
distributi
on
49
Multiple Effect Distillation (MED)
Multi-media
Filter
Dual Softeners
Break Tank
Heat
Exchanger
Hot Water
Sanitizable
Activated Carbon
Unit
To storage and
distribution
5 Micron
Prefilter
Hot Water
Santizable
Reverse Osmosis
Unit
254 nm UV
Optional pH
Adjustment
CEDI/IX
Multiple Effect
Distillation Unit
Storage and
Distribution Options
51
Hot Storage, Hot Distribution
steam
52
Hot Storage and Distribution
Most advantageous when:
1.
makeup water is generated hot
all or most use points need hot water
tightest microbial control required
Least advantageous when:
2.
all or most users need ambient temperature
water
makeup water is generated ambient
energy costs are high
53
Single Point of Use, Steamed
from hot loop
clean
steam
coolant
to point
of use
54
Use Point Heat Exchanger, Offline
Advantages
1.
no pressure drop impact on loop
no limit on number of units
Disadvantages
2.
sanitization required prior to use
flush water volume
55
Point of Use Installed in Subloop
restriction
orifice
from hot loop
coolant
to point
of use
56
Use Point Heat Exchanger, Subloop
Advantages
1.
no deadleg
no sanitization prior to use
Disadvantages
2.
pressure drop in loop required
number of units limited
57
Hot Storage, Cool and Reheat
steam
Reheat
Exchanger
Cooling
Heat Exchanger
58
Hot Storage, Total Cool and Reheat
Most advantageous when:
1.
hot generation
ambient use
tight microbial spec
little sanitization time
Least advantageous when:
2.
energy is costly
59
Hot Storage, Self-Contained Distribution
(90% of flow)
(10% of flow)
steam
Cooling
Heat Exchanger
60
Hot Storage, Recirculated Cooled
Subloop
Most advantageous when:
1.
hot generation
ambient use
energy cost is high
Least advantageous when:
2.
ambient generation
limited sanitization time
61
Heating / Cooling Costs
1.
100 GPM Purified Water Loop
2.
30 GPM average consumption
3.
800C distribution/250C at use points
4.
Reheat of all unused cold water
5.
$6.50 per 1 MM Btu heat (1000 lb. plant steam)
6.
$8.00 per 1 MM Btu cooling (chiller)
7.
20 hr. day/6 day week
62
Heating / Cooling Costs Example
1.
$1.74 MM 10 yr. operating cost
2.
10 % partial recirc./reheat reduces 10 year
operating cost by $1.56 MM
3.
65OC operation (total recirc) reduces 10
year operating cost by $474 K
4.
Ozonated storage/distribution reduces
hot/cold 10 year operating cost by $1.5+ MM
plus passivation savings
63
Ambient Storage, Ambient Distribution
coolant
coolant
Sanitizing / Cooling
Dual Purpose
Heat Exchanger
64
Ambient Storage and Distribution
Best utilized when:
1.
Sanitization method critical
2.
3.
generation ambient
usage ambient
microbial requirements less stringent
may be frequent
may have biofilm issue
Generation system microbial control
important
65
Hot Water Sanitization
1.
Proven history
2.
No chemical handling or disposal
3.
Minimal rinse period (limited downtime)
4.
Ability to automate
5.
Ability to validate dead leg exposure to
heat
6.
Significantly lower risk of product
contamination
66
Chemical Sanitization
1.
Low cost pharmaceutical systems only
2.
Chlorine / hydrogen peroxide / peracetic
acid
3.
Rinse periods required
4.
Verification of no residual disinfectant
for pharmaceutical systems
5.
Difficult to meet indicator organism
requirements without filtration
67
Steam Sanitization
No Chemical Handling or Disposal
Minimal Rinse Period (limited downtime)
Ability to Automate
Complete drainablity of system and flush required
Common in pharmaceutical WFI systems
Best when used in 316LSS systems
Possible in PVDF
1.
2.
3.
4.
5.
6.
7.
Requires continuous support
Requires significant expansion loops
Limited to 1400C
68
Ozonated Storage and Distribution
AIT
ozone
optional
ozone
destruct
unit
coolant
AIT
AIT
ozone
ozone
coolant
Ozone
Generator
Ozone destruct
UV unit
69
Ozonated Storage
Most advantageous when:
generation system product is ambient
most or all users ambient
energy costs are high
production allows relatively frequent
sanitization
microbial requirements are strict
(continuous sanitization of storage)
70
Ozonated Storage
Least advantageous when:
product/trace ozone compatibility issue
exists
periodic heat sanitization costs are less
(small loops)
continuous tank sanitization not required
71
Ozone
1.
Microorganism kill several logs faster than
chlorine
2.
Most bacteria killed in seconds
3.
Lyses cell wall - not dependent on diffusion
through cell wall
4.
Capable of organic oxidation including
endotoxin
Compatible with SS and PVDF
Effective at levels as low as 0.05 ppm
5.
6.
72
Ozone Removal
Dissolved
1.
Ultraviolet light (3X germicidal dose)
Activated carbon
Heat
Time
Gas
2.
Manganese dioxide catalytic device
Heat
73
Summary
1.
2.
3.
4.
5.
6.
International regulatory specifications vary
Little written detail cGMP requirements exist
FDA is the official cGMP body
Water quality requirements are easily met
with existing technologies
PW can be produced by many production
processes
WFI production methods limited
74
Summary
7.
8.
Systems must be continuously or
frequently sanitized for best microbial
performance
Energy costs can be minimized through
proper engineering
75
Thank You
Additional
information:
Gary Zoccolante
USFilter - Lowell, MA
508-746-5338
zoccolanteg@usfilter.com
76
