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