Critical measurements in pharmaceutical water

Critical Measurements in
Pharmaceutical Waters
Anthony C. Bevilacqua, Ph.D.
Mettler-Toledo Thornton, Inc.
Bedford, MA 01730 USA
www.mt.com/thornton

A3P 21st International Congress 1 October 14-16, 2008
Agenda
Pharmaceutical Water and the USP
What is the Purpose of Measurements? Critical Measurements?
Overview of Conductivity/TOC Requirements and Harmonization
Proposals/Changes to USP 〈645〉 and 〈643〉 General Chapters
Source water, Production, and Microbiology Requirements
Summary

Aqua Distillata (Distilled Water)
Aqua distilleteur vasis permundis, donec ejus duo circiter trientes
stillaverint. Aquam distillatum in lagena vitrea servato.
Let water be distilled in very clean vessels until about two thirds have come over,
which is to be kept in a glass bottle.
Printed in USP I (1820) by the
Pharmacopoeia of the United States of America

Why is Water Important?
Water is multi-functional
- Raw material
- Solvent
- Ingredient
- Reagent
- Cleaning agent (hot water or steam)
- Sterile/Packaged waters
8Sterile Water for Irrigation
8Sterile Water for Inhalation
8Sterile Purified Water
8Bacteriostatic Water for Injection
8Water for Hemodialysis
Water is the most widely used excipient in Pharmaceutical
Manufacturing

How do you "identify" water?
- Molecular weight 18.02
- Chemical structure
Strength
- ?
Identity, Strength, Purity, Impurities
How do you characterize its purity?
- Microbiological
- Organic (non-living)
- Inorganic
- Particulate
- Dissolved Gases
O
HH
Types of Impurities Characteristics Types of Tests
Microbiological living, organic, non-ionic sterility
Organic (non-living) non-ionic TOC
Inorganic ionic conductivity
Particulate insoluble, non-ionic filter/particle counter
Dissolved Gases ionic, non-ionic usually benign

What is the USP?
The USP is the U.S. Pharmacopeia.
It is a private, not-for-profit, non-governmental organization.
There are no political or governmental links.
It is dedicated to the development of quality standards for the benefit of
the public health.
The USP establishes standards for the benefit of public health…
they are legally enforced by the FDA.

Water Types in Pharmacopoeia
+Purified Water (containers)5
Pure Steam
Water (tap, well)
Water for Hemodialysis (bulk + containers)
Sterile Water for Irrigation (containers)
Sterile Water for Inhalation (containers)
Bacteriostatic Water for Injection (containers)
Sterile Purified Water (containers)
Sterile Purified Water (bulk)
Purified Water (bulk)
Highly Purified Water (bulk)
Water for Injection/sterilized (containers)
Water for Injection (bulk)
Water Type
+13
+12
++11
+10
+9
+8
+7
+6
+++4
+3
+++2
+++1
JP XVEP 6.0USP 31

Ammonium (mg/mL)
Nitrite
Sulfate
Chloride
0.5 (0.3 for control)0.50.5TOC (mg/L)
Note 1: All tests are maximum, unless otherwise stated.
Note 2: Microbiological testing is considered to be harmonized, with the exception noted that the EP test is written into the
Production section, and the USP test is contained in a non-compendial general information chapter
Note 3: Limits are temperature dependent
Residue on Evaporation (mg)
Oxidizable Substances (/100 mL)
Acidity/Alkalinity
0.1Heavy Metals (ppm)
0.2Nitrates (ppm)
0.250.250.25Bacterial Endotoxins (EU/mL)
1.3 (3 stage)1.3 (3 stage)1.3 (3 stage)Conductivity (µS/cm at 25°C)3
-10-Total Aerobic (cfu/100 mL)2
JP water specificationHuman consumption
US, EU, Japan, WHO
drinking waterSource Water
Distillation, RO with UF,
from Purified Water
Distillation
Distillation or suitable
process
Production Method
JPEPUSPAttribute1
Bulk Water for Injection(s) Requirements

Bulk Water for Injection(s) - in 2005
0.5Ammonium (mg/mL)
Not detectableNitrite
Not detectableSulfate
Not detectableChloride
0.50.50.5TOC (mg/L)
1.0/100 mLResidue on Evaporation (mg)
< 0.10 mL 0.02 KMnO4Oxidizable Substances (/100 mL)
Test with color indicatorsAcidity/Alkalinity
Not detectable0.1Heavy Metals (ppm)
Not detectable0.2Nitrates (ppm)
1.3 (1 stage)1.3 (3 stage)Conductivity (µS/cm at 25°C)3
US, EU, Japan, WHO
from Purified Water
Distillation
process
Production Method
JP XIVEP 4.0USP 28Attribute1

Bulk Water for Injection(s) - Today
0.5Ammonium (mg/mL)
0.5 (0.3 for control)0.50.5TOC (mg/L)
< 0.10 mL 0.02 KMnO4Oxidizable Substances (/100 mL)
US, EU, Japan, WHO
from Purified Water
Distillation
process
Production Method
JP XVEP 6.0USP 31Attribute1

Bulk Purified Water - Today
0.5Ammonium (mg/mL)
0.50.5 (optional)0.5TOC (mg/L)
Note 3: Limits are temperature dependent Note 4: Alternative to TOC
< 0.10 mL 0.02 KMnO4<0.1 mL4 0.02 KMnO4
Oxidizable Substances (/100 mL)
Bacterial Endotoxins (EU/mL)
100100100Total Aerobic (cfu/mL)2
US, EU, Japan, WHO
Distillation, ion-exchange,
UF, or combination
Suitable processSuitable processProduction Method
JP XVEP 6.0USP 31Attribute1

Agenda
Summary

How do you know if…
… you are removing/controlling ions, TOC, microbes, particulates, etc…?
… each purification step is functioning properly?
… the quality of the product is “suitable for its intended use”?
… the water chemistry has changed (and the water system is not flexible
enough)?
measure, measure, measure
Measurements assure the quality of the
PRODUCT and the PROCESS

UPW Make-up & Distribution System
Pretreatment
Heat
Exchanger RO
prefilter
2-Pass RO
MB
or
CEDI Degasifier
MB Polisher
0.5 µ UPW
Storage
Pump
Final Filter
0.1 µ
UV Sterilizer
0.2 µ
0.1 µ POU
filters
More
POU
Feed
water
Cl2 Inj.
Acid
Injection
Caustic
Injection
Measurements
Cond/Resistivity
pH
ORP
DO
TOC
Pressure
Flow
Total pts: ~25-40
MB Polisher

Process Analytical Measurements for UPW
Chemical Measurements
Conductivity/Resistivity
- compensated and uncompensated
TOC
Dissolved Gases
- Oxygen
- Ozone
Specific ions
- pH
- Sodium
- Magnesium, Calcium
Specific other
- Bisulfite or free chlorine
- ORP
- Silica
Physical Measurements
Temperature
∆P across filter
Flow rate (for % recovery)
Flow rate and return pressure
(through the distribution system)
Biological Measurements
Number of colonies/mL
Type of bacteria
Endotoxins

Performance Measurements at RO/DI System
Physical Measurements an example where physical measurements are
integrally related to unit performance
Inlet and outlet conductivity
Inlet and outlet pressure
Inlet and outlet flow rate
Flow rate and TDS/Conductivity






κ
κ
−×=
outlet
inlet
1100%Rejection








+
×=
rejectproduct
product
FF
F
100Recovery%
outin PPP −=∆
dtF(t)TDS17.12Grains
t
0
t ××= ∫

What are Critical Measurements?
Measurements of a process or a product that impacts…
Quantity of product
- average, daily, peak
Cost of product
- efficiency
- cost of production
- cost of maintenance
Quality of product
- safety
- purity
- out-of-spec investigations
Consistency of the product
Engineering focus
Uses in-process measurement tools and
controls while the product is being
manufactured.
Product focus - QA
Uses measurement tools after the product is
manufactured.
Bridge using
Process Analytical
Technology

What are Critical Measurements?
Measurements that are regulated…
for Purified Water and WFI…
Conductivity
Total Organic Carbon
Microbes
Endotoxins (WFI only)
Measurements to verify "No added substances", i.e., ozone
Product and Process Control
These real time, in-process measurements
permit control of product AND Process while
the product is being manufactured and used.

Agenda
Summary

Conductivity and TOC
Conductivity measurement in UPW is the measurement of total ionic
(conductive) impurity.
- Dozens of ions in water
- Sub-ppm and sub ppb
- Detectable by AA and other methods if specificity is needed
Total ionic screening method
No specificity
TOC measurement in UPW is the measurement of total organic (usually
non-conductive) impurity.
- Hundreds/thousands of organics in water
- Sub-ppb
- Not detectable by methods available today in UPW
Total organic screening method
No specificity

5. Conductivity Requirements
Prior to November 1996, existing chemistry tests date back to 1840. Chemistry
tests are qualitative, subject to bias, and off-line.
- Carbon dioxide
- Calcium
- Ammonia
- Chloride
- Sulfate
- Oxidizable Substances
- Heavy Metals
November, 1991 – Conductivity proposed to replace the chemistry tests.

USP 〈645〉 3-Stage Test Method
1. Measure in-line, non-temperature-compensated conductivity and temperature. Look
up conductivity limit for that temperature. If measured uncompensated conductivity is
less than conductivity limit, then Pass - Done. If not:
2. Lab Test : Equilibrate water sample with atmospheric CO2 : If
conductivity is less than 2.1 µS/cm at 25°C, Pass – Done. If not:
3.Lab Test: Saturate previous sample with KCl : Measure pH.
Look up conductivity limit for that pH. If measured conductivity
(from Stage 2) is < conductivity limit, Pass – Done. If not:
Fail

USP 〈645〉 Water Conductivity Stage 1 Limits
Stage 1 - on line - non-temperature-compensated
for USP Purified Water and WFI
0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.1
1.8
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
0 10 20 30 40 50 60 70 80 90 100
Temperature (°C)
UncompensatedConductivity(µS/cm)
Cl Model
NH3 Model
USP <645> Stage 1 Limit

EP Conductivity Limits - effective July 1, 2004
Separate Conductivity Limits for
EP Purified Water, Highly Purified Water, and WFI
0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.1
1.8
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
0 10 20 30 40 50 60 70 80 90 100
Temperature (°C)
Cl Model
NH3 Model

JP Water Conductivity Limits for PW & WFI
Same As USP - official Apr 1, 2006
0.6 0.8 0.9 1.0 1.1 1.3 1.4 1.5 1.7 1.9 2.1 2.2 2.4 2.5 2.7 2.7 2.7 2.7 2.9 3.1
1.8
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
0 10 20 30 40 50 60 70 80 90 100
Temperature (°C)
Cl Model
NH3 Model

Advantages of On-line, In-line Stage 1 Testing
Real-time process (conductivity and temperature!) information.
Immediate alarms and control options.
Data can be logged . . . providing a water history.
Easier and cost-effective.
Eliminates sample collection and transportation errors.
Temperature-compensated conductivity remains an excellent technique to observe
water quality changes.
Maintains the Quality Assurance by improving the integrity of the testing.
0.0
0.2
0.4
0.6
0.8
1.0
1.2
0 5 10 15 20 25 30 35 40 45 50
Conductivity(ℵS/cm)
off-line 2
off-line 1
on-line 2
on-line 1

〈645〉 Conductivity - Calibration & Performance
Meter Requirements
Reports uncompensated conductivity or resistivity.
Display resolution of 0.1 µS/cm minimum. 1 µS/cm resolution is unacceptable.
Verify performance to ±0.1 µS/cm by replacing sensor with traceable precision (0.1%)
resistor. For example: 100 kΩ resistor with 0.1 cm-1 cell constant should display 1.0 ± 0.1
µS/cm.
Temperature measurement circuit should be verified.
Sensor Requirements
Cell constant accurate and known to ± 2%.
Calibrate sensor in a solution with a stated conductivity (from NIST,
chemical supplier, etc...).
Calibrate sensor in a solution prepared to a specific conductivity (ASTM
D1125 standard or ultrapure water).
Calibrate sensor vs. another calibrated sensor (from mfgr. usually).
Temperature accurate to 2°C – effective USP 28

EP Conductivity Requirements - July 1, 2004
Sensor Requirements
“electrodes of a suitable material such as stainless steel”
“cell constant: within 2% of the given value determined using a certified
reference solution with a conductivity less than 1500 µS/cm.”
Meter Requirements
“resolution 0.1 µS/cm on the lowest range.”
“by means of precision resistors or equivalent devices, after disconnecting the
conductivity cell, for all ranges used for conductivity measurement and cell
calibration (with an accuracy of at least ±0.1% of the stated value, traceable to
the national standard).”
System Requirements (sensor and meter)
“If in-line sensors cannot be dismantled, system calibration may be performed
against a calibrated conductivity cell placed in proximity to the cell to be
calibrated in the water flow.”

Long Term Cell Constant Stability
0.090
0.092
0.094
0.096
0.098
0.100
0.102
0.104
0.106
0.108
0.110
Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06
Calibration Date
CellConstant(1/cm)
208859 PC
228403 PC
237855 PC
297063 MAX
P03013 MAX
Industrial, robust Conductivity sensors do not require frequent
calibration!

Harmonization: Conductivity Methods and Limits
Parameter USP EP JP CP
Conductivity test required yes yes yes 2007?
Eliminate chemistry tests yes no1 yes
Purified Water 3-stage test yes no yes
Purified Water test limits2 1.3 µS/cm 5.1 µS/cm 1.3 µS/cm
WFI 3-stage test yes yes yes
WFI limits2 1.3 µS/cm 1.3 µS/cm 1.3 µS/cm
Instrument requirements yes yes yes
Sensor accuracy ±2% ±2% yes ?
Sensor calibration method not specific not specific yes
Calibration solutions user selected user selected yes
Calibration Method works works yes
Compensation none none yes
Method tested yes yes yes
1 Heavy metals and nitrates tested required for EP; aluminum test required for dialysis solutions
2 at 25°C

Where does TOC come from?
Leachates and humic acids and other outside sources
- Large molecules
- Complex mixtures
- Some man-made waste… pesticides?
Degradation of the water system
- RO membranes
- Filters
- Ion-exchange resins
Formation within water system
- Biofilm?
particulates
most probable

On-Line TOC by UV Oxidation/Conductivity
Hg lamp emits 185 nm and 254 nm UV light
Light, chemicals, surfaces, and time move the reaction forward
Accurate conversion of temperature and conductivity is required
CxHyOz CO2 + H2O H2CO3 H+ + HCO3
-
UV
IR-based methods Conductivity-based methods
NO TOC sensor/analyzer/system measures TOC. All measure
something else, usually CO2!

〈643〉 TOC - Calibration & Performance
Limit of Detection of 0.050 mg C/L (50 ppb TOC)
Calibrate according to Manufacturer’s recommendations
Must distinguish inorganic carbon, i.e., CO2, HCO3
-
Must meet System Suitability testing periodically

Question: What is System Suitability Testing?
Answer: The process of challenging a TOC analyzer to convert sucrose
and p-benzoquinone to another detectable species (CO2) equally.
It is required by USP <643> and EP 2.2.44
What is System Suitability or SST?
Raw
Material Stock Solution
(50,000 ppb) Standard Solutions
(500 ppb)

PW, HPW, and WFI TOC Requirements
Procure sample. Measure TOC of test water, Ru.
USP: Water passes TOC test if Ru < Rs - Rw (~500 ppb).
EP: Water passes TOC test if Ru < 500 ppb.
- TOC testing required for WFI and Highly Purified Water
- TOC testing optional for EP Aqua Purificata (PW).
JP WFI
- Water passes TOC test if Ru < 500 ppb
- Water passes TOC test if Ru < 400 ppb - off-line (for control)
- Water passes TOC test if Ru < 300 ppb - on-line (for control)
JP Purified Water
- Water passes TOC test if Ru < 500 ppb (recommendation)

TOC Response
0
5
10
15
20
25
01-Jul 03-Jul 05-Jul 07-Jul 09-Jul 11-Jul
TOC(ppb)
16.0
16.5
17.0
17.5
18.0
18.5
Resistivity(MΩ-cm)
Control
Thornton
Thornto
Control

Impact of Real-Time Measurements
JN006 Test 071b - 4 days
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
1/7/05
12:00:00
1/8/05
0:00:00
1/8/05
12:00:00
1/9/05
0:00:00
1/9/05
12:00:00
1/10/05
0:00:00
1/10/05
12:00:00
1/11/05
0:00:00
1/11/05
12:00:00
Time
TOC(ppb)
4 days of analysis of MT-Thornton UPW system - shows ~3/4 hr
cycling of water system and 3 autobalance cycles

JN006 Test 071b - 1 day
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
1/8/05
0:00:00
1/8/05
3:00:00
1/8/05
6:00:00
1/8/05
9:00:00
1/8/05
12:00:00
1/8/05
15:00:00
1/8/05
18:00:00
1/8/05
21:00:00
1/9/05
0:00:00
Time
TOC(ppb)
an autobalance cycle

JN006 Test 071b - 3 hrs
4.00
4.20
4.40
4.60
4.80
5.00
5.20
5.40
5.60
5.80
6.00
1/8/05 0:00:00 1/8/05 1:00:00 1/8/05 2:00:00 1/8/05 3:00:00
Time
TOC(ppb)
DI tank filling from RO tank
DI system polishing

1-stage
RO
EDI
UPW
Storage
Pretreatment
Carbon
bed
RO
prefilter
1 µ
Pump
Final Filter
0.1 µ
UPW POU
Feed
water
Mixed
Bed IX
Softener
5 µShut Off
valve
RO
storage
RO POU
Pump
UV TOC
reduction
UV TOC
reduction
UV Sterilizer
Ultra Filter
TOC
Potable
water
Water System

Ozone as a "New" Sanitizing Agent
An excellent oxidizer
- Breaks DNA
- Prevents the proliferation of bacteria
Historically discouraged by FDA ~5-10 years ago
Used more and more today
- Low capital cost
- Low generating and modest operating costs
- No chemicals to dispose
- Preferred to "chemical" cleaning
Must comply with "added substances" rule.
- "It contains no added substances."
Heat is still the preferred method

Is Ozone (O3) an "Added Substance"?
MB
or
CEDI Degasifier
Ozone
Destruct
Pretreatment
Heat
Exchanger RO
prefilter
2-Pass RO
MB Polisher
0.5 µ UPW
Storage
Pump
Final Filter
0.1 µ
0.2 µ
0.1 µ POU
filters
More
POU
Feed
water
Cl2 Inj. Acid
Injection
Caustic
Injection
Measurements
Cond/Resist
pH
ORP
DO
TOC
Pressure
Flow
Ozone
Pre-Treatment System
Measure O3 here to insure
desired sanitant concentration.During operation, measure O3
here to insure "0" concentration.
Measure O3
here to insure
desired sanitant
concentration -
DURING NO
OPERATION.

Agenda
Summary

〈645〉 On-Line vs. Off Line Testing

〈645〉 Calibration Verification Step

〈645〉 Sterile Water Test Limits

〈643〉 Total Organic Carbon BriefingPF34(5) Sept-Oct 2008
In-Process Revision published in PF34(5) Sept-Oct, 2008.
Official USP32 (2009) - if approved by USP.

〈643〉 Excerpts PF34(5) Sept-Oct 2008
"A TOC measurement is not a replacement test for endotoxin or
microbiological control. While there can be a qualitative relationship between a
food source (TOC) and microbiological activity, there is no direct numerical
correlation."
"A number of acceptable methods exist for analyzing TOC. This chapter does
not limit or prevent alternative endorse, limit, or prevent any2S(USP31)
technologies from being used, but this chapter2S (USP31) provides guidance on
how to qualify these analytical technologies for use as well as guidance on
how to interpret instrument results for use as a limit test."
Historical information not relevant to the method deleted.

How many microbes are in 1 ppb TOC?
Assuming the following
- Microbe Density is 1 g/cm3
- 10% of microbe consists of carbon
- Radius of spherical microbe is 0.5 µm
Microbial counts in 1 ppb of TOC carbon
- 1 ppb TOC = 10-9g C/mL
- (10-9g C/mL )÷(5.2 x 10-14 g C/microbe) ≈ 19,000 microbes/mL
Purified Water: 100 cfu/mL is 0.050 ppb
WFI: 10 cfu/100 mL is 0.000050 ppb

〈643〉 Total Organic Carbon BriefingPF34(5) Sept-Oct 2008

〈643〉 and 〈645〉 Summary
〈645〉 Summary
- Conductivity limits are unchanged for bulk waters.
- Methods are unchanged.
- Added "system" verification step advised for conductivity.
- Tests added for Sterile waters and "packaged bulk" waters
〈643〉 Summary
- TOC limits are unchanged for bulk waters.
- Calibration and SST tests unchanged.
- TOC is not a replacement for micro testing.
Value of on-line measurements is written into the chapters.

Agenda
Summary

1. Source Water Requirements
USP: "It is prepared from water complying with the U.S. Environmental
Protection Agency National Primary Drinking Water Regulations or with the
drinking water regulations of the European Union, Japan, or with the World
Health Organization's Guidelines for Drinking Water Quality."
EP: "from water that complies with the regulations on water intended for human
consumption laid down by the competent authority."
JP: "prepared from Water".
What is the purpose of the Drinking Water Requirement?
- Prevent recycling
- Communicate with the water provider
- Test water regularly and seasonally
Start with Drinking Water - Recirculate, don’t recycle

2. "Method of Manufacture" Requirements
Purified Water
- USP, EP, JP permits production by distillation, reverse osmosis, de-ionization,
filtration, or equivalent means.
Water for Injection
- USP permits “distillation or a purification process that is equivalent or superior to
distillation in the removal of chemicals or microorganisms”USP27
- EP permits distillation only
- JP permits distillation or RO/UF
Highly Purified Water
- EP only, produced by RO, meets WFI
- Allowed for limited pharmaceutical applications
You must Distill to make WFI for a Global product

3. Microbiology Requirements
EP limits are ACTION LIMITS in Production section
- Purified Water…100 cfu/mL
- WFI……………..10 cfu/100 mL
USP limits are “recommended” in 〈1231〉 general chapter
- Same limits as EP
JP limits are enforced in drinking water requirements
- Same limits as EP
In practice, this is the most widely audited and monitored
attribute of Purified Water and Water for Injection

4. Endotoxin Requirements (WFI only)
<0.25 EU/mL Endotoxin (USP and JP)
<0.25 IU/mL Endotoxin (EP)
Same limits and same tests

Agenda
Summary

USP Summary for Bulk Waters
WFI shall be produced by distillation or proven validated methods.
Purified Water and WFI shall meet specific conductivity and TOC requirements.
〈645〉 Water Conductivity is a 3 stage conductivity test.
- permits on-line and off-line testing
- non-temperature-compensated conductivity measurements
- specific performance requirements for the instruments and sensors
〈643〉 permits on-line and off-line testing.
- permits on-line and off-line testing
- System Suitability Test is required for instrument qualification
- specific performance requirements
Microbiological "requirements" are written in a >1000 chapter.
Conductivity and TOC requirements for USP Bulk waters and very mature and
will change very little.

EP Summary for Bulk Waters
WFI shall be produced by distillation ONLY.
Purified Water and WFI shall meet specific conductivity and TOC requirements.
- same requirements as USP for WFI
- higher limits for Purified Water
Nitrates and Heavy Metals testing still required.
- Heavy metals testing deleted in 2008?
Calibration and performance requirements same as USP.
TOC testing fully harmonized with USP - almost.
Microbiology limits harmonized, but written in Production section of monographs.

Mettler-Toledo Thornton
Thank You!

Critical measurements in pharmaceutical water

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