THORNTON

Leading Pure Water Analytics

Confidence in Compliance

Pharmaceutical Water Compliance

for Global Pharmacopeia Requirements
Contents

Page

1. Water Purity Standards 3 T hornton was founded by Dr. Richard Thornton

(Professor at Massachusetts Institute of Technology,
2. What Is USP? 3
MIT) in 1964 and has been part of the METTLER
2.1 Conductivity and Total Organic Carbon (TOC) for TOLEDO Process Analytics Division since 2001. The
Monitoring the Purity of Water: 3 company’s market leadership has been demonstrated
by innovative analytical instruments and sensors
3. Goals of USP <645> 4
specializing in High Purity and Ultrapure Water
3.1 USP <645> Conductivity 4 applications found in various industries including:
Pharmaceutical, Biotechnology, Microelectronics and
3.1.1 Advantages of On-line Testing 4
Power Generation.
3.2 Temperature and USP <645> 5
3.3 <645> Conductivity Procedure 5 METTLER TOLEDO Thornton personnel are active in
3.3.1 Stage 1 5 various scientific organizations such as ASTM, ISPE,
PDA, AIChE, SEMI, and USP. Extensive research has
3.3.2 Stage 2 & 3 6
been conducted in:
3.4 Summary of Calibration Requirements for USP <645> 6
3.5 Recommended Process for Calibration 7 • Conductivity of Ultrapure Water
3.5.1 Transmitter or Measurement Electronics Calibration 7 • High Temperature UPW
• TOC and Ozone (O3)
3.5.2 Sensor Calibration 8
• Dissolved Oxygen and CO2
3.5.3 Typical Methods Used to Verify/Calibrate Sensor • Calibration and Temperature Compensation
Cell Constant 8
3.5.4 Typical Method Used to Verify/Calibrate Sensor
Temperature (RTD) 9
3.5.5 Calibration of Cell Constant Using Digital
Conductivity Sensors 9
3.5.6 Frequency of Calibration 9

4. Temperature and USP <1644> 10

ISM® Provides Much More Than
5. USP <643> Total Organic Carbon 11 a Measurement
Intelligent Sensor Management (ISM)
5.1 System Suitability Test (SST) 11
is a proven technology embedded in
5.1.1 The SST Procedure 11 a sensor, which outputs a robust digital
signal, retains unique factory and
6. Validation of Final Rinse for Clean in Place (CIP) 12 current calibration data and predicts
a sensor’s need for maintenance,
calibration or replacement.
7. EP, JP, ChP, IP and Other Pharmacopeias’
Requirements 14

8. Compliance with FDA 21 CFR Part 11 and

EC GMP Annex 11 17
8.1 When Is 21 CFR Part 11 Applicable? 17
8.2 System Access and Data Protection 17

9. METTLER TOLEDO Thornton Contributions to

Standards Development 18

2 METTLER TOLEDO Pharmaceutical Water Compliance

 1. Water Purity Standards
Water Purity Standards and USP

Purified Water (PW), Highly Purified Water
(HPW), Water for Injection (WFI), and Pure
Steam are used in Pharmaceutical
manufacturing processes around the world.
National and international authorities have
established water quality standards for Purified
Water and other grades of water. These key
authorities include:

United States Pharmacopeia (USP)

European Pharmacopeia (EP)
Japanese Pharmacopeia (JP)
Chinese Pharmacopeia (ChP)
Indian Pharmacopeia (IP)

2. What Is USP?
The United States Pharmacopeia (USP) is a non-governmental, official public standards-setting authority
for prescription and over-the-counter medicines, cosmetics, and other healthcare products manufactured
or sold in the United States. USP also sets widely recognized standards for food ingredients and dietary
supplements. It also sets standards for the quality, purity, strength and consistency of these products which
are critical to public health. USP’s standards are recognized and used in more than 130 countries around
the globe. These standards have helped to ensure public health throughout the world for close
to 200 years.

2.1 Conductivity and Total Organic Carbon (TOC) for

Monitoring the Purity of Water
 Conductivity and Total Organic Carbon (TOC) are measurements for ionic and organic impurity control in
bulk Purified Water, Water for Injection and the condensate of Pure Steam. Chapters <645> Water
Conductivity and <643> Total Organic Carbon of the United States Pharmacopeia provided the first test
methods for equipment verification, on-line process control and release of water to production. USP
specifications do not limit or prevent alternative technologies from being used, but provide guidance on
how to qualify these analytical systems, interpret instrument results and set standards for the measuring
instrumentation used for TOC and conductivity such as a System Suitability Test (SST), limit of detection,
instrument resolution and calibration requirements for sensor and transmitter or measurement electronics.

Pharmaceutical Water Compliance METTLER TOLEDO 3

 3. Goals of USP <645>
Goals of USP <645>

1. Ensure integrity of existing water quality

2. Replace outdated wet chemical tests
3. Quantify test results
4. Encourage on-line testing
5. Mitigate the amount of testing required
6. Improve testing reliability

3.1 USP <645> Conductivity

Bulk waters for pharmaceutical purposes include Water for Injection, Highly Purified Water, Purified
Water and Pure Steam. Most global pharmacopeias have stated requirements for producing these
waters. In the United States, the regulations for conductivity are addressed by the U.S. Pharmacopeia in
test chapter <645> which is harmonized with other global pharmacopeias. Conductivity testing is a
requirement for USP Purified Water, Water for Injection and the condensate of Pure Steam.
USP <645> is a 3-stage test method which entails either on-line or off-line testing. On-line conductivity
testing is covered by Stage 1, while Stage 2 and 3 represent off-line testing. In December 2008, USP
<645> was amended to encourage the use of on-line testing:

“On-line conductivity testing provides real-time measurements and opportunities for

real-time process control, decision and intervention. Precaution should be taken
while collecting water samples for off-line conductivity measurements. The sample
may be affected by the sampling method, the sampling container and environmental
factors such as ambient carbon dioxide concentration and organic vapors.”

3.1.1 Advantages of On-line Testing

There are several advantages for performing on-line testing. One key advantage is that with on-line
testing, errors associated with collecting, handling and transport of the sample are mitigated or
eliminated. In addition, as water is produced and consumed continuously, on-line testing enables the
collection of real-time data which can be recorded and analyzed providing real-time process information
and a complete water history. On-line testing provides a simple, cost-effective measurement alternative
to off-line testing.

Simplified Compliance
ISM simplifies regulatory compliance by
storing sensor calibration data internally
and reducing written record keeping.

4 METTLER TOLEDO Pharmaceutical Water Compliance

 3.2 Temperature and USP <645>
Goals of USP <645>
T emperature is a key parameter for observing changes in water quality as it can have a significant
impact on conductivity measurements of water samples. USP <645> describes the importance of
temperature this way:

“Because temperature has a substantial impact on conductivity readings of water

samples at high and low temperatures, many instruments automatically correct the
actual reading to display the value that would theoretically be observed at 25°C.
This is typically done through the use of a temperature sensor embedded in the
conductivity sensor and an algorithm in the instrument’s circuitry. This temperature
compensation algorithm may not be accurate. Conductivity values in this method
are non-temperature-compensated measurements.”

In other words, because temperature compensation algorithms between manufacturers lack
reproducibility, USP <645> requires conductivity measurements that are non-temperature-compensated.
METTLER TOLEDO Thornton instruments enable reporting uncompensated and compensated
measurements using the same transmitter and sensors.

3.3 <645> Conductivity Procedure

3.3.1 Stage 1

Stage 1 is intended for on-line measurement.

On-line temperature and non-temperature-compensated conductivity are measured. The measured

temperature value is rounded down to the next lowest 5°C interval and the adjusted temperature reading
is located on the table below. If the measured conductivity is not greater than the limit in this table, the
water meets the requirements for <645>.

Stage 1: Temperature and Conductivity Requirements

Temperature Maximum Conductivity Temperature Maximum Conductivity
(°C) (µS/cm) (°C) (µS/cm)
0 0.6 55 2.1
5 0.8 60 2.2
10 0.9 65 2.4
15 1.0 70 2.5
20 1.1 75 2.7
25 1.3 80 2.7
30 1.4 85 2.7
35 1.5 90 2.7
40 1.7 95 2.9
45 1.8 100 3.1
50 1.9

Pharmaceutical Water Compliance METTLER TOLEDO 5

 3.3.2 Stage 2 & 3
Goals of USP <645>

Off-line tests have different requirements and results can be more difficult to achieve. In both Stage 2
and 3, the sample is stirred (to equilibrate the water sample with atmospheric CO2) and the temperature
is adjusted to 25° ± 1°C. If the conductivity is less than 2.1 μS/cm, the water meets the requirements
of <645>.

However, if the water sample is greater than 2.1 μS/cm, the user proceeds to Stage 3. In Stage 3, the
sample temperature is maintained at 25°C ± 1°C. A saturated potassium chloride solution is added to
the water sample and pH is determined to the nearest 0.1 pH unit. If the conductivity reading from Stage
2 is not greater than the conductivity referenced for a given pH value (see Table 2 in USP <645>), it
meets the requirements of <645>. If either the measured conductivity is greater than this value or the pH
is outside the range of 5.0 - 7.0, the water does not meet the requirements of <645> for conductivity.

3.4 Summary of Calibration Requirements for USP <645>

The conductivity of water must be measured accurately using calibrated instrumentation. USP <645>
has calibration requirements for both the transmitter and measurement electronics as well as the sensor.
The requirements for transmitters or measurement electronics (for digital sensors) include:

• T emperature measurement circuit verified.

• Reports uncompensated conductivity or resistivity.
•D  isplay resolution of 0.1 μS/cm. 1.0 μS/cm resolution
is not acceptable.
• V erify performance to ± 0.1 μS/cm by replacing
sensor with traceable precision (0.1%) resistor.
For example: 50 kΩ resistor with 0.1 cm-1 cell
constant should display 2.0 ± 0.1 μS/cm.

Transmitter Requirements and METTLER TOLEDO Thornton Transmitters

USP Specification M800 (ISM®) M300 (ISM) M300 (Analog)
Resistors accurate to 0.1% of stated
accuracy, traceable to NIST or 0.05% - 0.1% NIST traceable
equivalent national authority
Instrument accuracy without sensor
±0.004 μS/cm (±0.3% of reading)
at 1.3 μS/cm is ± 0.1 μS/cm
Instrument display
0.001 μS/cm
resolution to 0.1 μS/cm
Must report non-temperature
Reports non-temperature compensated and temperature compensated
compensated conductivity or
conductivity or resistivity
resistivity

6 METTLER TOLEDO Pharmaceutical Water Compliance

 The USP <645> calibration requirements for conductivity sensors include:
Goals of USP <645>
• T emperature accurate to ± 2°C.
•C  ell constant accurate and known to ± 2%.
• Calibrate sensor in a solution with 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 usually from the same manufacturer.

3.5 Recommended Process for Calibration

In general, a complete measuring system consists of: the measuring electronics or transmitter, which
typically contain the measurement circuit, the sensor and the cable linking the sensor and transmitter.
The following parameters must be fully calibrated to produce a calibrated system:

1. The measuring electronics or temperature circuit

2. The measuring electronics’ resistance circuit
3. The sensor temperature element
4. The sensor cell constant
UniCond® Calibrator

Sensor Requirements and METTLER TOLEDO Thornton Sensors

USP Specification UniCond® Analog
Sensors Sensors
Cell constant accurate ± 1%
Cell constant accuracy: ± 2% using
reference solution (e.g. ASTM D1125
Calibration traceable to ASTM
or other reference solution)
D1125, D5391, and Ultrapure Water
± 0.1° C at 25°C
Temperature accuracy: ± 2°C
Temperature traceable to NIST

3.5.1 Transmitter or Measurement Electronics Calibration


When transmitters or measuring electronics are calibrated, it is important to
verify and calibrate all range resistors and the internal circuitry. This is
traditionally done through the use of a decade box or a manufacturer’s
calibration device. In these devices, traceable resistors are used to simulate
temperature and conductivity. Measured temperature and conductivity are then
compared to the traceable temperature and resistivity. Adjustments are then
made as needed to calibrate the electronic circuitry.

Transmitter Traceability

Pharmaceutical Water Compliance METTLER TOLEDO 7

 3.5.2 Sensor Calibration
Goals of USP <645>
Cell Constant: Although a sensor cell constant may have a nominal value
of, for example, 0.1 cm-1, the precise cell constant is typically calibrated
individually to achieve higher accuracy. This is done using a known
solution in comparison with another calibrated measuring system. Factory
calibrations of cell constant are certified and traceable to an ASTM
standard while temperature is traceable to NIST.

Sensor Traceability
Thornton 0.1 cm-1 Conductivity Sensor

Conceptual Drawing
of Cell Constant

Length 0.1 cm
1 cm
Conductivity Cell Constant = = = 0.1 cm-1
A Area 1 cm2

Smaller inner electrode Length – distance between electrodes

d
1 cm 0.1 cm 0.1 cm-1 Area – effective cross-sectional area of fluid between electrodes

3.5.3 Typical Methods Used to Verify/Calibrate Sensor Cell Constant

1 cm
A

Calibrating the cell constant of a sensor can be achieved using several methods.
d
1 cm
0.01 cm
1. Verification or calibration of the sensor vs. another calibrated sensor.
2. V erification or calibration of the sensor in a solution with a known conductivity. Conductivity solutions
for this purpose may be purchased or they may be prepared to a specific conductivity value using
ASTM standard methods or Ultrapure Water.

When calibrating the sensor cell constant, a calibrated transmitter and a similar cable length should
be used.

Easy Sensor Handling

ISM sensors are pre-calibrated,
providing error-free operation with
Plug and Measure simplicity.

8 METTLER TOLEDO Pharmaceutical Water Compliance

 3.5.4 Typical Method Used to Verify/Calibrate Sensor Temperature (RTD)
Goals of USP <645>
Calibrating temperature typically involves comparing the measured temperature with a reference
temperature. When verifying and calibrating temperature, a calibrated transmitter or measurement
electronics and a similar length of cable should be used and the temperature reference system should
be incorporated into the same fluid and container.

3.5.5 Calibration of Cell Constant Using Digital Conductivity Sensors

The UniCond® Conductivity/Resistivity Sensor advancement integrates the measuring circuit and the
physical sensor into a single unit. Sensor and measuring circuit are inseparable and they are factory
calibrated as a system at the same time, resulting in a single limit of error, the same as a traditional
analog sensor by itself. The digital transmitter in this case is not involved in the measurement circuit
and thus introduces zero error.

Compliance with USP <645> requires calibration of both the sensor cell constant as well as the measurement
circuit. The measurement circuit is traceable to NIST and the cell constant traceable to ASTM. Measuring circuit
of UniCond sensors are calibrated prior to assembly.

In the case of the UniCond Sensor, the measurement circuit is incorporated within the sensor itself and
not the transmitter, and the UniCond Calibration Module is uniquely suited to enable calibration of the
measurement circuit while installed in the process.

3.5.6 Frequency of Calibration

In order to comply with USP test guidelines and good metrology practices, calibration must be done
periodically. Most pharmacopeias, including the USP, do not specify a frequency for calibration; this is
left to the recommendations of individual manufacturers. Industry norms typically suggest that
calibration be performed annually.

UniCond Sanitary Sensor

Pharmaceutical Water Compliance METTLER TOLEDO 9

 4. Temperature and USP <1644>
Temperature and USP <1644>

Test chapter <1644> was recently released by the USP. This chapter provides technical guidance for
pharmaceutical users in the theory, operation, calibration, and maintenance of conductivity measurement
systems. One aspect of the chapter that requires consideration is the discussion regarding the use of
temperature compensation for controlling pharmaceutical water systems.

USP <1644> recommends the use of temperature compensation for all measurement points, except for
those required by USP <645>. USP <645> requires non-temperature compensated measurements for Water
for Injection (WFI) and Purified Water (PW), but only at the testing/reporting point. This is most often
located on the return loop to the tank after the last point-of-use. The European Pharmacopeia (EP) has the
same requirements as USP <645>, but permits temperature compensation at all measurement points after
suitable validation.

4.1 Why Should You Make a Temperature Compensated

Conductivity Measurement?
T he answer is for process control. Conductivity measurement is affected by water temperature. Temperature
compensation eliminates this effect on conductivity measurements and provides a fixed threshold for
controls and alarms. 25°C is recognized by the pharmaceutical industry worldwide as a standard reference
temperature. By compensating conductivity measurements of pure and ultrapure waters to this reference
temperature, the whole water system will be under full process control.

METTLER TOLEDO Thornton transmitters are flexible, with the potential to display temperature compensated
conductivity, non-temperature compensated conductivity, and temperature readings all from the same
conductivity loop. This means that the testing/reporting point on the return loop can report both the non-
temperature compensated conductivity reading and the temperature for the WFI and PW, while also
controlling the system using the temperature compensated measurements. Our transmitters offer a unique
USP alarm setpoint feature making compliance with USP <645> and USP <644> easy.

M800 Transmitter and UniCond

Sanitary Sensor

10 METTLER TOLEDO Pharmaceutical Water Compliance

 5. USP <643> Total Organic Carbon
USP <643> Total Organic Carbon

Total Organic Carbon is a measure of organic impurities present in pharmaceutical waters measured
as carbon. Organic molecules are introduced into the water from source water, from purification and
distribution system materials and from biofilm growing in the system.

A number of acceptable methods exist for analyzing TOC. USP Chapter <643> does not endorse or limit
one method over another, but it provides guidance on how to qualify these technologies and how to
interpret their results for use as a limit test. All methods must discriminate between inorganic carbon,
present in water from sources such as dissolved CO2 and bicarbonate and the CO2 generated from the
oxidation of organic molecules.

USP <643> uses the following criteria to establish acceptance of TOC instrumentation:

1. Must have Limit of Detection of <0.05 mg carbon/L or 50 ppb of TOC

2. Must be calibrated according to manufacturer recommendations
3. Must distinguish inorganic carbon, i.e., CO2, HCO3 from the CO2 generated from the oxidation
of organic molecules
4. M
 ust pass System Suitability Test (SST) periodically

5.1 System Suitability Test (SST)

 ecause organic carbon appears in various forms in nature and in water treatment processes,
B
a wide variety of oxidation states and chemical forms are found in sample waters. The purpose
of the System Suitability Test is to challenge the TOC instrument by verifying that it responds
equally to two types of organic chemicals that challenge its measurement capability. USP <643>
specifies these chemicals as Sucrose and 1, 4-Benzoquinone. Due to their different chemical
structure, Sucrose and 1, 4-Benzoquinone challenge the bond-breaking and oxidation capability
of the TOC measurement technology. USP <643> requires that SST be performed periodically
on a calibrated instrument.

5.2 The SST Procedure

1. Measure TOC of water used to prepare these solutions, Rw
(Rw should not exceed 0.1 mg C/L (100 ppb))
2. Measure TOC of 0.50 mg C/L (500 ppb C as sucrose), Rs
3. Measure TOC of 0.50 mg C/L (500 ppb C as p-benzoquinone), Rss
4. Response should be between 85 and 115%

Response = 100 x
( Rss - Rw
Rs - Rw )

5000TOCi Analyzer

Pharmaceutical Water Compliance METTLER TOLEDO 11

 6. Validation of Final Rinse for Clean in
Validation of Final Rinse

Place (CIP)

The challenge: the quality of the water for final rinse must equal the quality of the water used in production
and the user must validate the final rinse and quickly restore the system to production. The guideline for
cleaning and rinsing is that the final rinse used for equipment, containers, closures, and vessels should be
the same water quality used in the final stage of manufacturing of a pharmaceutical ingredient or an
excipient of a medicinal product.

The validation of the final rinse for CIP has been a significant bottleneck for pharmaceutical companies that
use off-line testing. When the final rinse needs to be validated in a lab or off-site, this can create delays in
the production cycle. For many pharmaceutical companies the rinse requirements are not clear and they
are either not testing at all or are rinsing for multiple cycles and are wasting expensive, high quality
pharmaceutical water. Shown below are the guidelines for the final CIP rinse and the pharmacopeia
regulations for Water for Injection (WFI) and Purified Water (PW). The cleaning guidelines focus on the
final rinse and not on the cleaning steps involved, therefore the validation must be of the water quality of
the final rinse itself, and not the CIP process.

METTLER TOLEDO Thornton’s 450TOC analyzer is a portable unit that can monitor TOC and conductivity
simultaneously to ensure that the final rinse meets pharmacopeia regulations for WFI and PW.

User Objectives for CIP:

• Monitor water quality during final rinse to verify quality

• Verify cleaning prior to placing in production
• Restore system to production as quickly as possible

Why Portable TOC Measurement?

• Simultaneously check TOC and conductivity

• Results in seconds, not hours
• Eliminate sampling errors from grab-sample
TOC C
• Reduce downtime by validating on-the-spot

Testing Vessels for CIP Final Rinse

12 METTLER TOLEDO Pharmaceutical Water Compliance

Validation of Final Rinse
Guidance for CIP Final Rinse
Cleaning/Rinsing of Equipment, Product Type Minimum Acceptable
Containers, Closures Quality of Water
Use same quality of water as used in the
Final rinse API
API Manufacture
Purified water or use the same quality of
Final rinse including CIP of
Pharmaceutical water as used in the manufacture of
equipment, containers and closures,
products – non sterile medicinal products, if higher quality than
if applicable
Purified Water
Initial rinse including CIP of
equipment, containers and closures, Sterile Products Purified Water
if applicable
Purified water or use the same quality of
Final rinse including CIP of
Sterile non-parental water as used in the manufacture of
equipment, containers and closures,
products medicinal product, if higher quality than
if applicable
Purified Water
Final rinse including CIP of
Sterile parental
equipment, containers and closures WFI
products
if applicable

Pharmacopeia Regulations for WFI and PW

Production Method Water for Injection Purified Water
(WFI) (PW)
Production Method Distillation Suitable process
US, EU, Japan, WHO US, EU, Japan, WHO
Source Water
drinking water drinking water
Total Aerobic (cfu/100 mL)2 10 NA
Total Aerobic (cfu/mL)
2
NA 100
1.3 (3 stage) at 25°C
Conductivity (μS/cm at 25°C) 1.3 (3 stage) at 25°C
EP 5.1 (1 stage)
TOC (mg/L) 0.5 0.5
Bacterial Endotoxins (EU/mL) 0.25 NA
Nitrates (ppm) – EP only 0.2 0.2
Bacterial Endotoxins (EU/mL) NA < 0.1 mL 0.02 KMnO4
4

Portable 450TOC Analyzer

Pharmaceutical Water Compliance METTLER TOLEDO 13

 7. EP, JP, ChP, IP and other Pharmacopeias’
Global Pharmacopeia Requirements

Requirements

The purpose of any country’s pharmacopeia is to provide a legal compendium* of enforceable

standards for product identity, purity and strength, i.e., its quality. In order to market products in a
specific country, that country’s compendia is required to be met. There are over 40 compendia
worldwide, with many compendia enforceable by multiple countries. As a result, if you are a producer
of products that are intended to be sold in multiple countries, you will need to meet the compendia of
multiple countries.

For the past two decades, the USP has been working closely with the European Pharmacopeia (EP)
and Japanese Pharmacopeia (JP) as a part of the Pharmacopeia Discussion Group (PDG). This group
pursues a path to “Harmonization” of monographs and general chapters. The definition of
Harmonization is “a pharmacopeia general chapter or other pharmacopeia document is harmonized
when a pharmaceutical substance or product tested by the document’s harmonized procedure yields
the same results, and the same accept/reject decision is reached.” The purpose of Harmonization is
to develop consistent specifications, tests/procedures and acceptance criteria for pharmaceutical
substances and drugs. The benefit to the pharmaceutical industry is the creation of one consistent set
of tests, not differing tests, such that one set of tests satisfy the identity, purity and strength
requirements of each country, thereby reducing and simplifying non-value added testing.

Harmonization is an ongoing process and its application to pharmaceutical waters has been
underway since 2000. The primary efforts to harmonize pharmaceutical waters have been towards
Purified Water and Water for Injection, the most common forms of water used in pharmaceutical
manufacturing. Because these waters are produced and used at every pharmaceutical manufacturer,
there is great industry incentive to support a harmonized set of tests for Purified Water and Water for
Injection. Since 1996, the USP has led the effort to replace former wet chemical tests with conductivity
and TOC limit tests along with proper instrumentation specifications. In 2000, the EP began to adopt
similar conductivity and TOC tests, although not identical to USP, and in the late 2000s, the JP also
began a similar adoption of these analytical tests.

The specific details of the individual pharmacopeias vary, but the “Big 3” pharmacopeias have gone
from no Harmonization in the 1990s to a very high degree of Harmonization. For example, the
chemical (conductivity and TOC) and microbial purity tests for WFI are harmonized completely,
although the permissible methods of production vary. On the other hand, the permissible methods of
production for Purified Water are consistent across the three regions, but the conductivity limits for EP
are higher than the conductivity limits in USP and JP.

14 METTLER TOLEDO Pharmaceutical Water Compliance

 As the world becomes smaller and industrial manufacturing becomes more global, other pharmacopeias
Global Pharmacopeia Requirements
such as the Indian (IP) and Chinese (ChP), to name only two, are becoming more relevant. While these
country’s pharmacopeias are not official members of PDG, they do follow where the other pharmacopeia
are going. These and other pharmacopeia are adopting the same type of chemical purity standards that
have been and are being led by the USP. While some chemical tests do remain, conductivity and TOC are
the primary indicators of chemical purity and water system process control.

*The tests or specifications described above are subject to change. Use the relevant and current pharmacopeia to
determine current specifications.

Bulk Purified Water and Water for Injection

Attribute USP EP JP ChP IP
Source Water for PW US, EU, Japan, Human JP water Potable water Potable water
and WFI WHO drinking consumption specification or or
water Purified Water Purified Water
Purified Water
Production Method Suitable Suitable Distillation, ion- Distillation, ion- Distillation, ion-
process process exchange, UF, exchange, or exchange, or
or combination suitable suitable
process process
Total Aerobic (cfu/mL) 100 100 100 100 100
Conductivity 1.3 (3 stage) 5.1 (1 stage) 1.3 on-line or 5.1 (1 stage) 1.3 (3 stage)
(μS/cm at 25°C) 2.1 off-line
TOC (mg/L) 0.5 0.5 (optional) 0.5 (0.3 for 0.5 0.5
control)
Nitrates (ppm) 0.2 0.2 Required
Acidity/Alkalinity Required
Ammonium (ppm) 0.2 Required
Oxidizable Substances Required
Water for Injection
Production Method Distillation or Distillation Distillation or Distillation Distillation
suitable RO with UF,
process from Purified
Water
Total Aerobic (cfu/100 mL) 10 10 10 10 10
Conductivity 1.3 (3 stage) 1.3 (3 stage) 1.3 on-line or 1.3 (3 stage) 1.3 (3 stage)
(μS/cm at 25°C) 2.1 off-line
TOC (mg/L) 0.5 0.5 0.5 (0.3 for 0.5 0.5
control)
Bacterial Endotoxins 0.25 0.25 0.25 0.25 0.25
(EU/mL)
Nitrates (ppm) 0.2 0.2 Required
Heavy Metals Required
Acidity/Alkalinity Required
Ammonium (ppm) 0.2

* Shaded boxes – no test required

Pharmaceutical Water Compliance METTLER TOLEDO 15

 Pharmacopeia Calibration and Test Requirements for Conductivity
Global Pharmacopeia Requirements

Conductivity Electronics (Resistance MeasurEment)

• Calibration required, frequency not specified, determined by owner, annual calibration accepted.
• Temperature measurement circuit to be verified.
• Instrument reports uncompensated conductivity or resistivity.
• Display resolution of 0.1 μS/cm minimum. 1.0 μS/cm resolution is unacceptable.
• V erify performance to ±0.1 μS/cm by replacing sensor with traceable precision (0.1%) resistor. For example:
50 kΩ resistor with 0.1 cm-1 cell constant should display 2.0 ± 0.1 μS/cm.
Conductivity Sensor
• Cell constant known to ± 2%.
• Calibrate sensor in a solution with a stated conductivity (from NIST or certified solution).

• Calibrate sensor in a solution prepared to a specific conductivity (ASTM D1125 standard or ultrapure water).

• Calibrate sensor vs. another calibrated traceable sensor – performed in-line or in-lab or return

to manufacturer.
• Temperature accurate to ± 2 °C.

Pharmacopeia Calibration and Requirements for TOC

TOC Requirements
• Instrument must have a 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 , from organic carbon.
• Must meet System Suitability Test (SST) periodically.
System Suitability Testing (SST)
• Measure TOC of water used to prepare these solutions, Rw. Not to exceed 100 ppb.
• Measure TOC of solution prepared to concentration of 0.50 mg carbon/L (as sucrose), RS.
• Measure TOC of solution prepared to concentration 0.50 mg carbon/L (as p-benzoquinone), RSS.
• The accepted frequency for testing is upon UV lamp change.
• Response shall be between 85 and 115%.

Response = 100 x
( Rss - Rw
Rs - Rw )

16 METTLER TOLEDO Pharmaceutical Water Compliance

 8. Compliance with FDA 21 CFR Part 11 and
21 CFR Part 11 and EC GMP Annex 11

EC GMP Annex 11

In 1997, the FDA issued 21 CFR Part 11 regulations to provide criteria for the acceptance of electronic
records in lieu of paper records with the intent to permit the widest possible use of electronic technology
while meeting FDA requirements. After Part 11 came into effect, there were many discussions within the
Agency and the pharmaceutical industry regarding possible misinterpretation of the regulations. Due to
the confusion, the FDA determined that the 21 CFR Part 11 regulations had to be reviewed and clarified.
In 2003, the FDA published the ‘Guidance for Industry’:

“ Under the narrow interpretation of the scope of part 11, with respect to records
required to be maintained under predicate rules or submitted to FDA, when persons
choose to use records in electronic format in place of paper format, part 11 would
apply. On the other hand, when persons use computers to generate paper printouts
of electronic records, and those paper records meet all the requirements of the
applicable predicate rules and persons rely on the paper records to perform their
regulated activities, FDA would generally not consider persons to be “using
electronic records in lieu of paper records”…”

8.1 When Is 21 CFR Part 11 Applicable?


The regulations only apply to instruments that store measurement data. Therefore, it does not apply to
METTLER TOLEDO Thornton transmitters as they only convey the measurement data to the PLC, SCADA,
etc. If a manufacturer’s instrument or system does store data that is used as a record and is susceptible
to unauthorized access, modification, or deletion, 21 CFR Part 11 is applicable and numerous criteria
must be addressed regarding the validation, security, and the qualification of these records. Please note
that 21 CFR Part 11 does not apply to all measurements, only for those in which a quality record is
retained. Additionally, the cost of ownership for maintaining an instrument or system that uses electronic
records is higher than one that does not due to the costs of validation, security and record qualifications
required to meet 21 CFR Part 11.

8.2 System Access and Data Protection

FDA 21 CFR Part 11 and EC GMP Annex 11 require protection from unauthorized access and alteration of
data. METTLER TOLEDO Thornton transmitters have multiple password levels to prevent unauthorized
access to the measurement inputs (sensor calibration factors) and the transmitter outputs (setpoints,
relays, analog outputs and digital outputs), and therefore comply with the access protections desired
within the 21 CFR Part 11 requirements.

Measurement transmitters and instruments usually do not store any electronic records or measurement
data that could be accidentally modified or deleted, and therefore transmitters meet the data protection
predicate requirements of 21 CFR Part 11. Transmitters and instruments simply provide the end-user the
ability to graphically view the measurement parameters over a pre-selected time period.

However, for any data transmitted by transmitters and instruments through one of several communication
protocols to a PLC, SCADA or Data Collection System (DCS) that is used for electronic record keeping in
place of paper records, 21 CFR Part 11 requirements would be applicable to the recording device (the
PLC, SCADA or DCS) on the water system, and not to the transmitter/instrument itself.

Pharmaceutical Water Compliance METTLER TOLEDO 17

 9. METTLER TOLEDO Thornton Contributions to
METTLER TOLEDO Thornton Contributions
Standards Development
When conductivity and TOC were proposed to replace wet chemical test methods in 1991, METTLER
TOLEDO Thornton was already in the forefront of industry leadership and standards development. ASTM
methods for conductivity were premised on work done by Dr. Thornton, our founder, in 1989 and prior
years. The company’s technical leadership continued with papers in 1994 by Drs. Morash and Bevilacqua,
and in 2004 by Drs. Licht, Light, Bevilacqua and Morash published in the peer-reviewed science journal,
Electrochemical and Solid-State Letters.

These technical articles, in conjunction with Thornton’s leadership in conductivity/resistivity measurement

systems for the microelectronics industry, paved the way for contributions to the USP. These papers were
focused on conductivity measurements for the microelectronics industry’s demand for ultra-high purity
waters. This industry’s need for large volumes of verifiable ion-free water was well-established,
as was Thornton’s leadership in the science of ultrapure water chemistry. Subsequently, the review of
Thornton’s scientific literature led the pharmaceutical industry and USP to seek analytical instrumentation
and water purification expertise from Thornton.

Compliance comes easy with METTLER TOLEDO

System
Confidence
ISM helps to ensure
production process
control for consistent M800 Transmitter M300 Transmitter
desired product
quality and yield. • Multi-channel (2 or 4) transmitter with multi-parameter • Multi-channel (2) transmitter with multi-parameter
measurement flexibility measurement flexibility
• Intelligent Sensor Management (ISM) • Intelligent Sensor Management (ISM)
• Plug and Measure simplicity •P  lug and Measure simplicity
• iMonitor – predictive maintenance •M  easurements are available within seconds
• Dynamic Lifetime Indicator of connection
• Trending graphics for all sensors •M  eets all pharmacopeias’ requirements for calibration
• Assured compliance with pharmacopeia regulations
Quick and easy installation thanks to Plug and
Simple menu operation with unparalleled performance Measure sensor capabilities.
and accuracy.

18 METTLER TOLEDO Pharmaceutical Water Compliance

 In 1994, our effort began with the conversion of chemical tests into a relevant conductivity limit test, i.e.,
METTLER TOLEDO Thornton Contributions
if you passed the conductivity test, you would necessarily pass all of the six existing chemical tests. The
adoption of this conductivity test has since replaced these six chemical tests. Likewise, with the technical
challenges posed by temperature compensation, Thornton developed a methodology to create a set of
on-line, temperature-dependent, conductivity limits, thereby allowing one to make conductivity
measurements at the process temperature without temperature compensation.

In 2000, the USP created the Pharmaceutical Waters Expert Committee, a newly-formed expert
committee with the responsibility of developing and maintaining the legal definitions for water
monographs and its related test chapters. The USP elected a current METTLER TOLEDO Thornton staff
member as its Chair for a 5-year term, and then was re-elected him for another 5 years from 2005-2010.
This expert committee, as a stand-alone group, is now concluded, but the “water oversight” responsibility
now lies with the same METTLER TOLEDO Thornton expertise on the USP Chemical Analysis Expert
Committee.

The work done by METTLER TOLEDO Thornton and the leadership of the USP led to the expansion of the
conductivity and TOC tests of the USP. These tests, known as <643> Total Organic Carbon and <645>
Water Conductivity, led to the adoption of these same analytical limit tests in the EP, JP and other
pharmacopeias around the world. Today, these specific tests done for global pharmacopeias are
premised on the pioneering work of Dr. Thornton and his successors over the last 50+ years.

Thornton’s Intelligent Sensor Management (ISM®)

5000TOCi with ISM UniCond® with ISM Ozone with ISM

• Complete process control and precise
data trending
• Plug and Measure functionality
• Instant notification of excursion
• Simplified record keeping for SST and CAL
• Trouble-free maintenance
• Robust, reliable design virtually free from
moving parts
• Compliant with all pharmacopeias
Delivering the power of an analyzer with the
convenience of a sensor.
• Conductivity Factory Calibration data stored
internally in sensor
• Plug and Measure functionality
• Integral high-performance measuring circuit
• Robust digital output signal
• Complete calibration for pharmaceutical
compliance
Calibration tracked by iMonitor (M800) to
ensure compliance.
• Rapid, accurate response
• Easy maintenance with drop-in membrane
• Plug and Measure functionality
• Positive zero detection
• Assured compliance with “no added
substance” rule
Confidently monitor complete sanitization
and confirm ozone destruction.

Pharmaceutical Water Compliance METTLER TOLEDO 19

Got a pharmaceutical waters question?
Ask Jim Cannon, our industry expert.

Visit us online for frequently asked pharmaceutical waters questions on

regulations, applications and calibration.

4www.mt.com/jim-knows-best

www.mt.com/ism-pharma
For more information

Mettler-Toledo Thornton, Inc.

900 Middlesex Turnpike, Bldg. 8
Billerica MA, 01821 USA
Phone +1 781 301 8600
Fax +1 781 301 8701
Toll-free +1 800 510 PURE (US & Canada only)
thornton.info@mt.com

Subject to technical changes

© 03/14 Mettler-Toledo Thornton, Inc.
58 087 004 Rev C 03/14