THORNTON

Leading Pure Water Analytics

Best Practice

METTLER TOLEDO
Process Analytics

TOC, Microbial,
Conductivity,
Resistivity,
and Ozone
Measurement
­Solutions

Pharmaceutical Waters Guide

for Regulatory Compliance, Analysis and Real-Time Release
Contents

Page

Pharma Waters Overview

The Preparation of Pharmaceutical Waters 3
Pharmacopeia Overview 9 The METTLER TOLEDO Pharmaceutical Waters Guide
provides you with a valuable and convenient informa-
Industry Trends for Pharmaceutical Waters 11
tional resource for Pharmaceutical Water production,
with insights into the applications integral to producing
Process Analytical Technology and Intelligent
these waters. This booklet offers vital information on
Sensor Management
topics including water purification technologies and
Ensuring Pharmaceutical Water Compliance in a system capabilities, critical measurements, global
PAT Environment 12 pharmacopeia regulations, and the latest technologies
to assist you in the design, operation, control, valida-
Total Organic Carbon tion, and compliance of your water systems.
Total Organic Carbon Measurement
is a Key Control Point for Pharmaceutical Water Systems 18 METTLER TOLEDO is dedicated to providing our phar-
maceutical industry customers with solutions for
Improving Water System Performance
measurement, monitoring, and control while assuring
Continuous Real-Time TOC Measurements 20
regulatory compliance, for all liquid analytics mea-
The Value of Measuring TOC surements. Decades of industry leadership in the
in CIP and Cleaning Validation Applications 23 process analytics environment ensure that METTLER
Case Study: Real-Time TOC Analysis TOLEDO can provide accurate and reliable measure-
Safeguards Water Purity 24 ments with robust solutions that meet the demanding
needs of this innovative industry.
Microbial
Real-time Microbial Monitoring
for Pharmaceutical Water Systems 26
Five Process Control Advantages
of On-line Microbial Detection 28
Case Study: On-line Microbial Instrumentation
for Real-time Monitoring and Control 29

Conductivity/Resistivity
Ensuring the Absence of Ionic Impurities
with Conductivity/Resistivity Measurements 31
Calibration Solutions for Pharmaceutical Waters 32
Publisher / Production
Case Study: Clean in Place Systems Manufacturer Mettler-Toledo Thornton, Inc.
Relies on METTLER TOLEDO 33 900 Middlesex Turnpike
Billerica, MA 01821
Ozone USA

Reliable, Cost-effective Sanitization Images

the Power of Ozone 34 Mettler-Toledo AG
Bosch Packaging Technology
Application and Control of Ozone Sanitization Getinge
for Pharmaceutical Waters 35 Christ Pharma & Life Science GmbH
Veolia Water
Case Study: Critical Ozone Measurement
USF Water Purification GmbH
in Purified Water Systems 38 Suncombe Ltd.
istockphoto.com
Data Integrity dreamstime.com
Data Integrity in Regulated Environments
Subject to technical changes
ALCOA+ for Pharmaceutical Waters 40 © Mettler-Toledo AG 12/2018

2 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 The Preparation of Pharmaceutical Waters
Pharma Waters Overview

While the public con­siders municipal water to be

“pure”, the pharmaceutical market considers municipal
water (feedwater) just the starting point in producing
pure water. Water is the most widely used excipient in
pharmaceutical manufacturing, and pharmaceutical
water is a multi-functional resource, crossing all disci-
plines in the pharmaceutical industry. Water is used as
a raw material, solvent, ingredient, reagent, and clean-
ing agent, and is produced in a variety of “pure” forms.

Purified Water (PW) and Water for Injection (WFI)

used in pharmaceutical processes are produced on
site from the local potable water, which has been
produced by the treatment of the feedwater.

Today’s pharmaceutical companies have invested

considerable capital in state-of-the-art instrumentation,
purification equipment, storage and distribution loops,
and importantly in the calibration and certification of
their water systems. By understanding water, its sour-
ces and impurities, and the capabilities and limitations
of purification methods, a water system can be de-
signed to meet not only pharmaceutical companies’
requirements but to meet global pharmacopeia
regulations.

Global pharmacopeia requirements for PW and WFI

1. Source water requirements
2. Method of Manufacture requirements: The purpose of this chapter is to provide a synopsis of
a. PW – any method but must meet quality source waters, purification methods, and measure-
standards ment technologies to maintain quality and certification
b. W
 FI – USP – Distillation or method equal of a pharmaceutical water system.
or superior; EP – Distillation or Reverse
Osmosis coupled with DI and/or UF; JP – Source water requirements
Distillation or a combination of RO/F; ChP
and IP – Distillation only “It is prepared from water complying with the U.S.
3. Microbiology requirements Environmental Protection Agency National Primary
4. Endotoxin requirements (WFI and Pure Steam) Drinking Water regulations or with the drinking
5. <645> Conductivity ­water regulations of the European Union, Japan, or
6. <643> TOC with the World Health Organization’s Guidelines for
7. No Added Substance rule Drinking Water Quality.” USP 40

Pharmaceutical Industry
METTLER TOLEDO Best Practice
3
 The feedwater source for a municipality can be from mined by weighing a sample of the feedwater before
Pharma Waters Overview
a surface water or a ground water supply. The impuri- and after evaporation.
ties vary in each source and some of the primary diff-
erences are shown below; Microbial
Bacteria, viruses, and pyrogens (endotoxins).
Ground waters Surface waters
High mineral content Lower mineral content Particulates
Low organic level High organic level Sand, dirt, and decay material.
High hardness level High total dissolved
solids level Organics
Less temperature Wide temperature Organic matter is a broad category that includes both
variation variation natural and man-made molecules containing carbon
and hydrogen. All living matter in water is made up
Because the quality and characteristics of the feedwa- of organic molecules. The most common are by-­
ter supply have an important bearing on the purifica- products of vegetative decay such as tannins, lignins,
tion, the pharmacopeias define the source water for and humic acid. By knowing the variety of contaminants
the production of PW and WFI. The pharmaceutical in the water and the removal capabilities of the different
facility should communicate regularly with their water available purification processes, a system
provider and request an annual water test report for the can be designed that will produce the water quality
feedwater. To further the understanding of the feedwa- required for a pharmaceutical facility. There are a range
ter and what technologies are required to purify it, of purification technologies and we have provided below
below are the categories of contaminants found in a a brief description of the major purification techniques.
water supply.

Contaminants in feedwater
The impurities found in water can be categorized into
six major classes: dissolved ionized solids, dissolved
ionized gases, dissolved non-ionized solids (organ-
ics), particulate matter, bacteria/algae, and pyrogens.
Feedwater varies significantly in purity both from one
geographical region to another, and from season to
season.

Total dissolved solids (TDS)

A measure of the total of organic and inorganic salts
dissolved in water, obtained by drying residue at 180°C.
Organic molecule
The sum of all ions in a solution is often approximated
by means of electrical conductivity or resistivity mea- Major water purification technologies
surements. TDS measurements are commonly used to The chart shown below is a summary of the removal
assess reverse osmosis unit performance. capabilities of different purification technologies versus
the contaminants commonly found in water.
Total ionized solids and gases
Concentration of dissolved ions in solution, expressed PW and WFI for pharmaceutical use are produced via
in concentration units of NaCI (sodium chloride). This a combination of different purification technologies. As
determines the operating life of ion exchange resins with the source water, each pharmacopeia defines the
used in water purification, and is calculated from m
­ ea- methods of production, but for PW the technologies
surements of specific resistance. Gases (carbon diox- utilized are the decision of the system designer, with
ide and oxygen) affect the water quality and system the only requirement being that the water meets the
performance. pharmacopeia regulations for quality. For WFI, to meet
the pharmacopeia requirements of USP, EP and JP the
Total solids WFI can be produced by distillation or alternative
Total solids in water include both dissolved and sus- means, but for ChP and IP it must be distillation. The
pended solids. The quantity of total solids is deter- final purification process must be d­ istillation.

4 Pharmaceutical Industry
METTLER TOLEDO Best Practice
Pharma Waters Overview
Major Classes of Contaminants
E = Excellent (capable of Dissolved Dissolved Dissolved Particulates Bacteria/ Pyrogens/
complete or near total Ionized Ionized Organics Algae Endotoxins/
removal)
Solids Gases Viruses
G = Good (capable of removing
large percentages)
P = Poor (little or no removal)
Purification Process
Distillation E G/E (1) E E E E
Deionization (EDI) E E P P P P
Reverse Osmosis G(2) P G E E E
Carbon Adsorption P P(3) E/G (4) P P P
Micron Filtration P P P E P P
Sub Micron Filtration P P P E E P
Ultrafiltration P P G(5) E E E
U.V. Oxidation P P E/G (6) P G(7) P

(1) The resistivity of the water is dependent on the absorption of CO2.

(2) The concentration is dependent on the original concentration in the feedwater.
(3) Activaled carbon will remove chlorine by adsorption.
(4) When used in combination with other purification processes special grades of carbon exhibit excellent capabilities for removing
­organic contaminants.
(5) Ultrafilters, being molecular sieves, have demonstrated usefulness in reducing specific feedwater organic contaminants based on the
rated molecular weight cut-off of the membrane.
(6) 1
 85 nm UV oxidation has been shown to be effective in removing trace organic contaminants when used post-treatment.
(7) 254 nm UV sterilizers, while not physically removing bacteria, have bactericidal or bacteriostatic capabilities limited by intensity,
­contact time and flow rate.

Purifying the feedwater for use in the pharmaceutical In reverse osmosis for pharmaceutical water produc-
industry requires a series of steps. The objective is to tion, a membrane is also used for the separation of
remove the impurities in the feedwater while minimiz- contaminated water. Membranes can be made from
ing additional contamination from the components of cellulose acetate, polyamide, polysulfone, or a variety
the purification system, the storage tanks, the distri­ of proprietary formulations. Two configurations are
bution system, and from possible biofilm growth. common: “hollow fiber” and “spiral wound”. Hollow
Selection of the correct purification technologies and fiber membranes look like a group of drinking straws
the instrumentation to monitor the system are critical gathered into a bunch, the spiral wound resemble a
to success. helix.

Reverse osmosis Because the quality of water produced by a reverse

Reverse osmosis is best understood when related to osmosis apparatus is directly dependent upon the
osmosis itself. In one of the experiments performed by quality of the input water and because effective remo-
everyone in first year chemistry, a semi-permeable val of ions today exceeds 97%, reverse osmosis is
membrane (a membrane that is permeable to water widely used as a pretreatment process to purify feed-
but not to salt) is used to separate two solutions; a water before introduction into an ion exchange unit or
saline solution and pure water. The pure water will flow a distillation system.
through the membrane to dilute the saline solution.
This is osmosis. When pressure is applied to the sa- Distillation
line solution, the natural process of osmosis can be Distillation is the oldest form of water purification and
overcome and even reversed. With sufficient pressure, has been utilized by humans since we first boiled wa-
pure water can be forced out of the saline solution ter in a cave. It is a unique process because it remo-
through the membrane and into the pure water side of ves the water via a phase change and leaves behind
the vessel. This is reverse osmosis. the impurities. In distillation, water is heated to its

Pharmaceutical Industry
METTLER TOLEDO Best Practice
5
Pharma Waters Overview

boiling point and undergoes the first of two phase Deionizers are generally available in two forms: a two-
changes, from a liquid to a vapor. The solid ionic ma- bed and a mixed-bed configuration. In the two-bed
terials, the particulates, the microbials, endotoxins, configuration, the cation and anion resins are in two
and most of the dissolved organic contaminants are discrete columns or in two discrete layers in the same
left behind in the boiler. The pure steam is then passed column. The advantage of the two-bed deionizer is
through a cooling coil where it undergoes a second that it can purify a greater volume of water than a
phase change from a vapor back to a liquid. For the comparable mixed-bed system; however, they produce
production of WFI, the pharmaceutical distillation sys- lower quality water.
tem is normally fed water that has been pretreated by
a variety of other technologies. The pretreatment is The mixed-bed deionizer contains an integral mixture
used to reduce the costs of maintenance on the distil- of anion and cation resins packed in a single column.
lation system and to ensure the quality of the distillate. Only mixed-bed deionization can produce water with a
Distillation is the only purification method that removes resistivity of 0.055µS/cm, which is theoretically ioni-
100 percent of b­ iological materials whether bacterial, cally pure.
viral, or p­ yrogenic.
Ion exchange technology is designed to remove ion-
Deionization ized or charged material from water. Even though
Deionization or ion exchange is a process also mistak- water will be ionically pure after the deionization pro-
enly called demineralization. The Encyclopedia of cess, the water will still contain non-ionized solid and
Chemical Technology defines deionization as: gaseous materials (organics), bacteria, viruses, and
pyrogens. These are not ionically charged species and
“The reversible interchange of ions between a solid cannot be removed by ion exchange processes.
and a liquid phase in which there is no permanent
change in the structure of the solid.” Electrodeionization
Electrodeionization (EDI, also known as EDR, CDI, and
Ion exchange involves the use of a resin composed of CEDI) is a technology that combines ion exchange
small spherical beads of a styrene polymer, cross- resins, ion-selective membranes and an electrical cur-
linked with divinylbenzene with chemically bonded rent to remove ionized contaminants from the water.
functional groups on the surface. For exchange of pos- Reverse osmosis is typically used before EDI to ensure
itive ions (cations), a resin called strong acid cation is that the EDI stack is not overloaded with high levels of
used. This resin makes available a hydrogen ion (H+) salts. Usually, reverse osmosis removes about 97% of
for exchange purposes. The exchange of negative ions ions. EDI will remove 99% of the remaining ions as
(anions) uses strong base anion resin. Here, a hydro- well as carbon dioxide, organics, and silica. In electro-
xyl ion (OH-) is available for exchange. deionization, the water passes through multiple

6 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 chambers filled with ion exchange resins held between
Pharma Waters Overview
cation or anion ­selective membranes. Under the influ-
ence of an electrical field, the anions and cations
migrate across the membranes to the anode and cath-
ode. Typically, EDI product water has a resistivity of 11
to 18.2 MΩ-cm (at 25°C) and a total organic carbon
(TOC) content below 20 ppb. Bacterial levels are mini-
mized because the electrical conditions within the
system inhibit the growth of microorganisms.

Carbon adsorption
In adsorption, the organic impurities in water form a
low-energy chemical bond with the surface of acti-
vated carbon. Because adsorption is a technique for
removing only organics and chlorine, it is most often para­meters need to be utilized to control and monitor
used as a pretreatment to remove large amounts of the system are critical.
organic impurities prior to other purification processes.
Activated carbon is very effective at removing chlorine Conductivity/resistivity is an electrical measurement
and other oxidants at rates of 2 to 4 times the chemi- of the number of ions in water and is presented as
cal weight of the oxidant. By removing the oxidants, either a conductance or resistance measurement. The
the opportunity for microbial growth is increased and pharmaceutical industry is required to report the con-
must be controlled and ­monitored. ductance of their PW or WFI. TOC is the deter-
mination of the total organic carbon level of the water
Ultraviolet light and is also a required measurement by international
Ultraviolet light at the 254nm wavelength is used as a pharmacopeia regulations. The chart on the next page
bactericide. This wavelength disrupts the ability of bac- provides some guidance for the parameters that
teria to reproduce. UV at 185nm will break down orga- should be used for control and monitoring of a phar-
nic contaminants to CO2 and water for subsequent maceutical water system.
removal by ion exchange.
Calibration and maintenance of the pharmaceutical
Filtration water purification system
Filtration can be performed by one of two methodolo- Once the water system is installed, qualified, and vali-
gies, either depth filtration or membrane filtration. dated a preventative maintenance and calibration
Depth filters can be made of sand in a container or of program must be developed and executed. Calibration
fiber wound around a core. Both methods mechani- of the measurement parameters is required by the
cally strain out sediment and particulate matter. pharmacopeia. Periodically, the local or international
inspecting authorities will inspect all pharmaceutical
Membrane filtration, on the other hand, is physical water treatment systems to ensure that the pharma-
straining by a single layer of membrane material. The ceutical facility complies with local or international
membrane material is produced from man-made res- regulations. Ultimately, the pharmaceutical company is
ins and can be either hydrophobic or hydrophillic. The responsible for validation and ongoing calibration of
pore size is tightly controlled and therefore absolute the water system to make sure that it meets pharma-
removal of particulates with diameters larger than the copeia requirements and passes the inspector’s audit.
pore size can be achieved. In pharmaceutical systems,
filtration is normally limited to the pretreatment section Summary
because although filters trap contaminants, it is possi- This chapter discussed the impurities commonly found
ble for bacteria to pass through a membrane filter. in water. We have also detailed water purification tech-
nologies and the measurement parameters required for
Controlling and monitoring the water purification monitoring a water system. By understanding feedwa-
system ter and the water purification system, a consistent sup-
Once the feedwater source is known and the purifica- ply of Purified Water or Water for Injection can be
tion technologies have been selected, knowing what ensured.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
7
Pharma Waters Overview
Parameters
Unit Process Cond % Temp TOC pH ORP Flow % Micro- Endo- Press, DO O3 Turb- Volt. Amps
Resist Rej. Rec bial toxin Level idity (VDC) (mA)

Particle Filtration

Catridge Filters • • •

Media Filters • • • •

Softeners • • • •

Dechlorination •

Carbon (GAC) Filters • • • • •

SB S, SMB S Inj. - *PID Control *

Break Tank • •

Chemical Addition

pH Adj. (Acid/Caustic Inj.) -

*
*PID Control

Neutralization Tank - *PID Control * * •

Nano and Ultra Filtration • •

Reverse Osmosis

Single Pass • • • • • • • • •

Two/Three Pass • • • • • • • • •

Desalination • • • • • • • • •

Ion Exchange

MB (Auto, Service) • • • • •

CEDI, EDI, EDR, CDI • • • • • • •

Distillation • • • •

Ozone (Injection or destruction) •

UV 254 (Microbial control) /

•
(ozone destruction)

UV 185 (TOC destruct) •

Degasifier • • •

Final Filtration • •

DI Storage Tank • • • • •

Storage Tank • • • • • •

Distribution Loop (*for WFI Loops) • • • • • * • • •

Pure Steam • • •

CIP Final Rinse Verification

• • • *
(*WFI used)

* Only available with PID control.

  Overview of recommended parameters for different unit processes.

8 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Pharmacopeia Overview
Pharma Waters Overview

The United States Pharmacopeia (USP) d­ efines sev- The two commonly used grades of pharmaceutical
eral types of water for pharma­ceutical use, as water are PW and WFI. The requirements are very sim-
follows: ilar; however, WFI has some additional preparation
and microbiological requirements:
• Purified Water
• WFI is usually prepared by distillation, although
• Sterile Purified Water (SPW) other final purification steps are possible depending
• Water for Injection on the pharmacopeia.
• Sterile Water for Injection (SWFI)
• Bacteriostatic Water for Injection •W  FI meets all the requirements for PW, and includes
• Sterile Water for Inhalation a specification for bacterial endotoxins (pyrogens).
• Sterile Water for Irrigation • Also, the microbial limits (or recommended levels)
• Sterile Water for Pure Steam are lower for WFI than for PW by a factor of 1,000.

The production of Purified Water and its requirements defined by different Pharmacopeia

“Purified Water is…”

US Pharmacopeia (USP): “… obtained by a suitable process”
European Pharmacopoeia (EP): “… prepared by distillation, by ion exchange, by reverse
osmosis or by any other suitable method”
Japanese Pharmacopoeia (JP): “… purified by ion exchange, distillation, reverse osmosis,
ultra filtration or by a combination of these methods”
Chinese Pharmacopoeia (CP): “… obtained by distillation, by ion exchange or by reverse
osmosis”
Indian Pharmacopoeia (IP): “… prepared by distillation, by means of ion exchange or by
any other appropriate means”

Pharmacopeia Requirements for Purified Water

USP EP JP CP IP****
Conductivity (µS/cm) <1.3* <5.1* <2.1* <5.1* <1.3*
TOC (µg C/L, ppb) <500 <500** <500 <500 <500
Bacteria (cfu/mL) <100 <100 <100 <100 <100
Nitrates (ppm) NR <0.2*** ND 0.06 0.2
Heavy Metals (ppm) NR <0.1*** NR <0.1 <0.1
pH NR NR NR 5.0-7.0 NR

* Limit is for 25°C. Stage 1 limits are temperature dependent. See table below.
** Test is optional. May be replaced by Oxidizable Substances Test.
*** Not required if the WFI conductivity requirements are met.
ND – Not detectable
NR – Not required

Pharmaceutical Industry
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Pharma Waters Overview
USP <645> Stage 1 Requirements
For non-temperature compensated conductivity measurements
Temperature °C Maximum Temperature °C Maximum
Conductivity µS/cm Conductivity 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

The production of Water for Injection and its requirements defined by ­different
­Pharmacopeia

“Water for Injection is…”

US Pharmacopeia (USP): “…distillation or a purification process that is equivalent or
superior to distillation”
European Pharmacopoeia (EP): “… distillation or reverse osmosis coupled with DI and/or UF”
Japanese Pharmacopoeia (JP): “… prepared by distillation or by a combination of reverse
osmosis and ultrafiltration”
Chinese Pharmacopoeia (CP): “… prepared by distillation”
Indian Pharmacopoeia (IP): “… obtained by distilling”

Pharmacopeia Requirements for Water for Injection

USP EP JP CP IP
Conductivity (µS/cm) <1.3* <1.3* <1.3*, 2.1 off line <1.3* <1.3*
TOC (µg C/L, ppb) <500 <500 <500 <500 <500
Bacteria (cfu/100 mL) <10 <10 <10 <10 <10
Endotoxin (EU/mL) 0.25 0.25 0.25 0.25 0.25
Nitrates (ppm) NR <0.2** ND 0.06 0.2
Heavy Metals (ppm) NR NR NR <0.1 Required by PW
pH NR NR NR 5.0-7.0 NR

* Limit is for 25°C. Stage 1 limits are temperature dependent.

** Not required if the WFI conductivity requirements are met.
ND – Not detectable
NR – Not required

10 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Industry Trends for Pharmaceutical Waters
Pharma Waters Overview

The high purity water treatment industry has progressed and changed significantly in
recent years.

Major trends include:

• Establishment and global harmonization of pharma- • Real-time microbial detection
copeia water regulations • Installation of new systems outweigh replacements
• Increased industrial safety and environmental and upgrades of existing systems
regulations • Added regulatory emphasis on on-line measure-
• Industrial multi-national companies (MNC) seek ments for “real-time process control, decision and
international integrated supply solutions intervention”
• Green engineering has improved energy efficiency • Increased emphasis on proactive and preventive
and significantly increased demand for reclaimed maintenance instead of reactive and hurried repairs
and recycled water • Single-use components and systems utilization is
• There is a shift from chemical treatment (except increasing with low cost disposable technologies.
ozone) to heat treatment The evolving requirements for measurement compo-
• Ozone (gas) is increasingly being used to sanitize nents and systems will continue to be met by METTLER
water systems TOLEDO Thornton with progress in instrumentation
• Process engineers prefer total solutions from a technology, innovative Intelligent Sensor Management
­single source (ISM™ ) and real-time control.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
11
 Ensuring Pharmaceutical Water Compliance
PAT/ISM

in a PAT Environment
The quality and safety of pharmaceuticals and biologics rely on the purity of water used in
their production. Increasingly stringent pharmacopeial requirements and the intro­duction of
new initiatives such as Process Analytical Technology (PAT) and Quality by Design (QbD)
places added challenges to life sciences companies. A new analytical sensor technology,
Intelligent Sensor Management, offers advanced process ­control to simplify the achieve-
ment of PAT goals, and to ensure the quality of pharmaceutical waters at all times.

Water for Injection, Purified Water, Pure Steam Con-

densate, Water for Hemo­dialysis, Sterile Water for
Injection, etc…: the variety of pharmaceutical waters
and water systems means their production is becom-
ing an increasingly specialized process that requires
highly dependable instrumentation.

In 2002, the FDA launched a new initiative called

“Pharmaceutical cGMPs for the 21st Century: A Risk-
Based Approach.” This scheme has led to the FDA
encouraging the adoption of Process Analytical Tech­
nology tools as a mechanism for ­designing, analyzing,
and controlling pharmaceutical manufacturing pro-
cesses for the purpose of making safer, compliant
products more efficiently with less dependence on end-
product testing. PAT encourages manufacturers to
develop a complete understanding of the process by
determining and defining the Critical Process
Parameters (CPPs), and monitoring them accordingly in
a timely manner, preferably with at-line or in-line instru-
mentation. This concept is particularly critical for water and control water production and quality. Some of
production as water is the most widely used raw mate- these in-process measurements include conductivity,
rial and excipient by every producer worldwide. In TOC, dissolved ozone, pH, ORP, silica, turbidity, flow
addition, water production is a 24/7/365 operation and rate, % rejection, tank level, temperature, and
the water is a continuously manufactured material, not pressure.
typically produced in batches that can be sequestered,
so constant monitoring is essential for continuous man- When a water system is designed, these measurements
ufacturing ­operations. are required for the water system to verify functionality
and performance of each purification step (IQ and OQ).
Process control vs. product control During water system production, the process owners
The importance of water monitoring and analysis dur- monitor these various measurements throughout the
ing and after production is not in doubt; however, the purification process to ensure that each step in the pro-
viewpoints on the merits of end product water testing cess is working properly. An example of the dozens of
and water system process control vary according to measurements throughout a purification system is
function. The owner of the water system (Production or shown below. For example, temperature is a CPP to
Engineering) has process analytics measurements demonstrate proper thermal sanitization (in a hot loop),
and physical measurements throughout the water sys- or differential pressure across a filter is a key measure-
tem from the incoming feedwater to pretreatment to ment to determine the proper time to change the filter.
purification to final distribution, in order to measure

12 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 PAT/ISM
1. Pre-treatment Water treatment can be
Feed Multi-media Softener GAC divided into three stages:
Water Filter
C pH
1. Pre-treatment
Cartridge 2. Purification
Filter
(1-5µ) UV 3. Storage and Distribution
Break
Tank
C
C

2. Purification 3. Storage and Distribution

RO Unit Ultra Filtration Electrodeionization
Unit (EDI) PW or HPW
C pH RMS
C
UV TOC
O3
C pH C
Storage C
Points
Tank
Distillation TOC of
for WFI
RMS Use

C TOC RMS

Measurement Points C Conductivity TOC TOC pH pH RMS Microbial Detection

Schematic of a Pharmaceutical Water Preparation System

The purpose of end product quality testing is to make being used (or has already been used) in production
certain that a sample of the batch/lot is safe, meets is safe and meets specifications at the time of use. A
compendial standards, and is of a consistent and ac- traditional method of achieving this has been to sam-
ceptable quality. The term “quality” is often used but not ple the water system at all use points on a timely ba-
defined. In the case of high purity waters such as Puri- sis. Depending on the size and design of the water
fied Water and WFI, “quality” usually means that spe- system, and the risk to the final drug product, Quality
cific requirements for conductivity, TOC, microbial Assurance collect samples from use points 1-3 times/
count, and endotoxins (WFI only) are met and found to day, possibly more or less frequently. For a facility
be acceptable to ensure water quality and consistency, with 50-100 use points, this requires significant re-
as water is a key ingredient. Depending on the local sources to accomplish TOC and conductivity testing.
pharmacopeia, other chemical tests may be required. Testing more samples per day assumes more cost
and resources and additional delays, but the user
The Quality Assurance group, responsible for end prod- feels at less risk. Testing fewer samples or use points
uct quality testing, will test the water according to gen- lowers costs, but carries more risk.
eral test chapters USP <643> Total Organic Carbon,
USP <645> Water Conductivity, and other specific tests Physicochemistry of measurements in high purity
that have traditionally been performed in the laboratory. pharmaceutical waters
This is where water differs from other pharmaceutical The challenges with measuring high purity pharma-
products. Most pharmaceutical products are produced, ceutical waters are not confined to frequency and
inspected, tested, and released in a batch/lot process. costs of lab testing. The waters themselves pose ex-
Water production is not a batch process. Water is pro- ceptional analytical problems when trying to measure
duced continuously, it is re-circulating constantly, and it the “quality” of the water in a lab environment, espe-
is often consumed 24/7. There is no opportunity or de- cially for conductivity and TOC measurements. The
sire to quarantine the water while QA testing is being typical conductivity of Purified Water or WFI may be
conducted. As a result, the water is used in production, anywhere from 2.0 μS/cm down to 0.055 μS/cm (0.5
at some risk, while (or before) the testing is completed. - 18.2 MΩ-cm) as measured in the water system pip-
ing or tank. However, when that water is removed from
The challenge to Quality Assurance is to test the water the distribution system, collected in a clean container,
frequently enough to have confidence that the water and transported to the laboratory, the conductivity of

Pharmaceutical Industry
METTLER TOLEDO Best Practice
13
 the cleanest water increases to ~0.8-1.2 μS/cm with under these conditions. While there remains a clear
PAT/ISM
exposure to air, even in the cleanest environments. distinction in the conductivities of the two on-line data
sets, the two off-line data sets are indistinguishable
This increase is due to the immediate reaction of ambi- from each other. The off-line samples have a wider
ent CO2 with water to make carbonic acid (H2CO3). degree of variability (not measurement noise, but im-
H2CO3 is a weak acid which partially dissociates to H+ purity noise) when going from on-line to off-line, resul-
and HCO3- ions, and the immediate creation of these ting from variable amounts of ambient CO2.
ions causes the conductivity to increase to ~1 μS/cm.
You cannot control or prevent this reaction with a natu- Also, the small increase in conductivity in on-line 1 at
rally-occurring molecule such as CO2. In addition, there sample 35, from 0.055 μS/cm to ~0.07 μS/cm is
are risks of organic vapors (perfume, human breath, completely undetectable in the off-line sample. In ap-
soaps) and contamination from all components used to plications where ultra-low ionic control is critical to the
transport samples. Any miniscule residue of cleaning process, an on-line measurement is the only approach
reagent or fingerprints on the container will adversely for detecting small changes.
affect the sample.
Similar results are observed for TOC measurements.
But the increase in the conductivity due to CO2 also ob- Samples of water collected in a container, after expo-
scures the true quality of the water as measured by sure to the environment, always have a higher TOC
conductivity. An example of this is based on a METTLER measurement than those measured in the on-line
TOLEDO Thornton R&D study of two types of water (on- pipe. In this case, it is not CO2 that causes the
line 1 and on-line 2, see Figure 1). Both are high purity increase: the water is so pure under these circum-
samples <0.2 μS/cm (>5 MΩ-cm), but there is a clear stances (typically <50 ppb, often <10 ppb) that it is
distinction between on-line 1 and on-line 2. Further, a the container cleanliness (soap residue, fingerprints,

1.2

1.0

0.8

0.6 off-line 2
off-line 1
on-line 2
0.4 on-line 1

0.2

0.0
0 5 10 15 20 25 30 35 40 45 50

Fig. 1: Comparison of on-line and off-line conductivity measurements of two high purity water samples

very small increase in conductivity of on-line 1 is de- etc.), organic vapors in the air, technician’s breath,
tected at sample 35. Both of these samples are mea- perfumes, etc. that always result in a higher reading
sured in real time, inside the on-line water system distri- from the off-line sample.
bution loop, without exposure to air, using the same
instrumentation. With regard to conductivity and TOC measurements in
high purity waters, there is not a problem with the ­lab-
The other two samples of water (off-line 1 and off-line oratory instrumentation or procedures; it is the sample
2) are the same waters as measured on-line, and mea- that has changed.
sured with the same sensor and transmitter, except that
they are measured 5 minutes after dispensing into a Benefits of “intelligent” on-line process analytics
clean container. The increase in conductivity for both for compendial high purity waters
sample types is completely understood since this is a While many measurements described above are used
result of the ambient CO2 in the environment. However, to control the water system, conductivity and TOC
there is a loss of information about the water quality measurements are the most closely monitored attributes

14 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 that indicate the water purification system is under dules, to avoid costly unplanned process downtime.
PAT/ISM
control for ionic and organic impurities. For process Consumable sensors such as pH electrodes benefit
control benefits, water system engineers insist that from ISM predictive indicators which identify sensor life
these be on-line, real-time measurements. Measure- status (aging) and time until maintenance. Service and
ments made an hour or a day later do little to control calibration intervals for the exchange of consumables
a continuously operating water purification system. can be scheduled in advance, saving time and money.
Since conductivity is a highly temperature-dependent
measurement, these conductivity measurements ISM addresses limitations of traditional analog
should also be temperature-compensated for the best sensors
process control practices (and according to USP Intelligent Sensor Management helps to eliminate
<1644> Theory and Practice of Electrical Conductivity issues for maintaining water system compliance. For
Measurements of Solutions). example:
• Sensor failure: The Dynamic Lifetime Indicator (DLI)
Intelligent Sensor Management (ISM®) is an exclusive and Time to Maintenance (TTM) tools offer specific
METTLER TOLEDO innovation in process measurement, data warnings that a sensor is aging or needs
which supports regulatory initiatives such as PAT by maintenance.
improving in-line and on-line process control with in- • Calibration date planning: ISM sensors inform in
telligent digital sensing and communications and real- advance of an upcoming calibration to avoid
time process analysis. missed or late calibration.
• Provide critical regulatory information: Electronic
ISM is an advanced digital sensor technology that in- documentation demonstrates that required tests
cludes predictive diagnostics, sensor calibration away have been performed with data to support regula-
from (or as part of) the process, Plug and Measure tory compliance.
start up, and electronic documentation. These features • System calibration: The METTLER TOLEDO Thornton
provide users with a better understanding of their pro- UniCond Calibrator and Pharma Waters Verifier are
cess with greater reliability, process safety and effi- the only tools that permit calibration of both the digi-
ciency; lower cost of ownership; and improved trace- tal sensor and the measurement circuit to ensure the
ability. measurement system is in compliance with global
pharmacopeia standards.
For conductivity and associated temperature measure-
ments, UniCond™ sensors with ISM technology store Plug and Measure – swiftly exchange pre-calibrated
unique factory and user sensor calibration information sensors to save time and cost
and increase measurement accuracy with in-line cali- One of the unique features of ISM technology is the
bratable electronic circuitry within the sensor and di- ability of each sensor to maintain its own calibration
gital communication to the transmitter. Total organic dataset, allowing the user to perform a calibration at a
carbon sensors with embedded digital conductivity location other than where the sensor is installed, if
sensors with ISM save previous calibration and system necessary. With this feature comes the ability to pre-
suitability records, while displaying time to c­ alibration calibrate sensors in a controlled environment rather
and time to maintenance reminders. that at the actual process. Pre-calibrated sensors may
then be exchanged at the measurement point in mini-
ISM technology permits TOC sensors to display long- mal time. Sensors can be calibrated in batches and
term Peak and Average readings from the water stored with their fresh calibration data until needed in
system, simplifying compliance record keeping by the process environment.
identifying two measurement points, peak and aver-
age, which are configurable for up to 24 hours of data. With real-time sensor status data available at any
In addition, continuous measurements are monitored time, the process can run more efficiently and critical
and displayed. This combination of Peak and Average measurement loops can be monitored for potential
and continuous TOC measurements support the PAT faults. ISM can also help to identify those sensors that
initiative and facilitate real-time control of CPPs. could possibly become the cause of the next unsched-
uled downtime. Sensor status information, such as
In addition, an ISM sensor’s individual performance is sensor aging, helps optimize maintenance intervals;
monitored continuously during operation to predict thus, the operator need intervene only when action is
maintenance requirements, including calibration sche- required.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
15
 ISM provides a built-in counter to track CIP and SIP ISM sensors are available for the following parameters:
PAT/ISM
cycles • conductivity (temperature)
Digital ISM sensors have a built-in Clean-in-Place • TOC
(CIP) and Steam-in-Place (SIP) counter, which detects • pH
when the sensor is exposed to thermal cycles. Upon • ozone
connection to an ISM transmitter, the status data from
the digital sensor is automatically loaded into the Transmitters and sensors with ISM capabilities provide
transmitter. When the maximum limit of thermal cycles the tools necessary to take full advantage of the benefits
allowed at this particular measurement point is ex- of digital on-line measurements. Critical points through-
ceeded, an alarm condition is raised. As a result, a out a system are monitored and controlled on-line with
sensor that could potentially fail in the process is iden- data provided locally at point of use, or remotely.
tified and cannot be utilized. Additionally, there is no
need to manually record each sensor’s CIP/SIP history, Conclusion
as the number of cycles is stored in the sensor itself. From a total cost of ownership perspective, the appli-
cation of on-line measurement systems in pharma-
­ceutical waters production represents a different cost
allocation than laboratory sampling. The cost basis
for laboratory sampling includes the cost of sampling
materials, clean containers (utilities cost for hot clean
water), and labor (for documenting sampling loca-
tions, and collecting and measuring samples).
Typical sampling regimens may include 1-3 samples/
day for all use points. Even when there are few sam-
ples and use points this still needs to be done
consistently every operating day. However, after the
cost of installation of the online transmitters, the data
is transmitted for free thereafter via a data collection
system. Therefore, with on-line measurements there
are significant labor/time savings that can be used
for more critical operations.

M800 ISM iMonitor displays sensor status On-line measuring allows for continuous measure-
ments at selected critical points, and especially at
Multi-parameter ISM transmitters provide simulta- point of use (POU) locations. End product analysis
neous measurement parameters ensures product quality in real time. According to
METTLER TOLEDO Thornton offers a complete array of USP <645>: “The selected sampling instrument
digital sensors, and a broad combination of process location(s) must reflect the quality of the water
control sensors can be utilized on a single multi-chan- used.” In this case, the measurement point may be
nel instrument, thereby reducing the need for multiple on the return to the storage tank after the last POU.
types of transmitters, multiple spare parts, multiple If the water quality meets regulatory requirements
control panel installations, and differing user inter- on the return, it is within specification at the previ-
faces. All METTLER TOLEDO ISM sensors provide ous POUs.
enhanced measurement performance while commu-
nicating vital information for process management and The single greatest advantage of on-line measure-
control in real time. ments is removal of uncertainty about product

16 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 quality. For the off-line QA systems, these end-control A low risk, simple, cost-effective alternative is to use
PAT/ISM
measurements are made an hour, a day or longer continuous on-line measuring instruments with the
after the samples are collected. When there is an out- predictive diagnostic abilities of Intelligent Sensor
of-specification result for TOC, for example, costly Management. Such systems produce measurement
investigations commence and multiple decisions results every second to monitor the whole water sys-
need to be made regarding the water and the product tem for real-time process control, a goal of PAT, and in
that came in contact with the water since it was last addition, monitor sensor “health” for significantly im-
tested. proved production safety.

M800 transmitter monitors multiple ISM sensors M800 transmitter displays real-time trending, peak and average TOC

Pharmaceutical Industry
METTLER TOLEDO Best Practice
17
 Total Organic Carbon Measurement
Total Organic Carbon

is a Key Control Point for Pharmaceutical Water Systems

The control of organic impurities in pharmaceutical

water systems is often misunderstood. The waters p­ ro-
duced in these systems come into contact with hu-
mans (and animals) through ingestion, injection,
transplants, transdermally, and via other medical pro-
cesses. It is often thought that the organic impurities in
the water must be kept low to protect the patient. In
fact, we ingest (and inject, transplant, etc.) organics all
the time through food, drink, and organic medicines.
Any residual organics in pharmaceutical waters are Organic structure
miniscule relative to the amount we eat, drink, or take
as medicines. that USP used to regularly receive from end-users) is,
“I perform on-line TOC measurements – can I stop
There are two principal reasons why the pharmacope- doing microbial testing?” The answer is “no”. Since
ias require total organic carbon measurement and 2008, USP has been very precise in the chapter (643)
control in PW and WFI systems. Firstly, the quantity Total Organic Carbon.
and trending of TOC are key indicators of the over-
all purification process control. Secondly, TOC is a vital “A TOC measurement is not a replacement test for en-
food source for bacteria, and there can be a qualitative dotoxin or microbiological control. While there can be
relationship between TOC and bacterial counts. a qualitative relationship between a food source (TOC)
and microbiological activity, there is no direct numeri-
A water purification system starts with drinking water cal correlation.”
as a raw material and produces a compendial water
(PW, HWP, WFI) in a continuously-operating series of At best, TOC measurement is an indicator of the micro-
purification processes (see “Pharma Waters bial and endotoxin control, but it is not a replacement
Overview”). Each purification process is designed to for those tests.
remove a specific type(s) of impurity such as particles,
hardness (Ca2+ and Mg2+), free chlorine, organics, met- For example, assume that 0.5 µm spherical microbes
als, gases, microbes, etc. in order to generate a water consist of ~10% carbon and has a density of 1 g/mL.
that is safe and proper to use in pharmaceutical tests, If the water has 500 ppb TOC and all of the TOC is
processes, and products. Measurements such as dif- bacteria, this would be ~106 microbes/mL, or approxi-
ferential pressure and % Recovery indicate the mately 10,000x the WFI limit for control of microbes!
efficiency and performance of an RO system. In this Another way to state this is the following: at the 10
regulated environment TOC measurement is not just a cfu/100 mL limit for WFI, the amount of TOC in that
required measurement of the finished water, the TOC sample is 0.00005 ppb! In other words, TOC mea­
value is a key indicator of the overall system purifica- surements cannot be used to count bacteria, but they
tion process. A low and stable TOC is a signal that the can be used to monitor and control the total water
carbon bed, reverse osmosis, downstream filters, elec- purification process.
trodeionization, and other individual purification steps
are properly purifying the water. Not only does the TOC This philosophy can also be adapted to processes that
measurement indicate a low TOC value for the water, it utilize water for cleaning. While a variety of acid and
also indicates a level of process control of the manu- caustic solutions are often used to rinse piping and
facturing (purification) system. vessels for Clean-in-Place (CIP) application, the typi-
cal final rinses of the hardware is with PW or WFI.
Another misunderstood reason for TOC measurement Historical methods for validating the piping/vessel
is that they are related to microbial counts. A question cleanliness and health are the use of swab samples to
that is regularly discussed at science meetings (and collect residue and then perform HPLC analysis. These

18 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 results take hours or days if extensive sample prepara- to the quality of water entering the system, then the
Total Organic Carbon
tion is required. But the motivation to reduce costs by bulk effluent and vessel is clean. [Note – This ap-
reducing system downtime has caused the industry to proach does not ensure that some chemicals have not
ask, “Can I determine if the system is clean in a more adhered to the walls of the system. However, the regu-
efficient manner?” A common approach is the use of lar acid/caustic cleaning and sanitary designs do con-
TOC and conductivity measurements as the final water firm that there are no residual chemicals.]
rinses are occurring. If the TOC and conductivity of the
effluent (water leaving the system) is equal or similar

Meet USP <643> and EP Regulatory Requirements with METTLER TOLEDO Products
Pharmacopeia Requirement USP <643> / EP/JP Specifications METTLER TOLEDO Product
Performance
6000TOCi
4000TOCe
450TOC
Limit of detection 0.050 mg/L <0.001 mg/L
Calibration Required NIST traceable
Distinguish inorganic carbon Required Measures initial conductivity to
from TOC determine IC
Meet system suitability 85 – 115% Typical performance is 95-100%
On-line or off-line measurements Either Capable of on-line and off-line

Pharmaceutical Industry
METTLER TOLEDO Best Practice
19
 Improving Water System Performance
Total Organic Carbon

Continuous Real-Time TOC Measurements

Safeguarding water quality at points of use necessitates rapid identification of total
organic carbon excursions. On-line, continuous flow TOC sensors ensure that even brief
excursions will not be missed.

Organics are introduced into natural water systems by

leachates in soil, typically from the decomposition of
vegetation, animal waste, and soil runoff. Organic
compounds in water are a concern at all levels of water
purity from potable water to pure waters used in the
manufacture of pharmaceuticals.

The source water used for the production of Purified

Water and Water for Injection is drinking water as indi-
cated in the major pharmacopeia. Potable water quality
can vary seasonally according to climatic changes and
municipal treatment strategies, which results in varying
TOC concentrations. In pharmaceutical manufacturing,
organics are a contaminant that needs to be controlled
as they are a food source for bacteria in the water puri-
fication system and can contaminate the final product.

A change in the TOC load in the water system can be

the result of fluctuating TOC in the source water, degra-
dation in the water system components, a drop in the
efficiency of the water purification system or develop-
ment of biofilm. This change can potentially influence
microbiological control. Because variations within a
water system can often occur both suddenly and unex-
pectedly, rapid detection of deviations in system per-
formance is critical for the purpose of minimizing TOC
load impact.
ings through quick detection and isolation of system
Continuous measurements faults. Continuous flow TOC sensors provide real-time
For this discussion, a continuous measurement is de- measurements that minimize the effect of excursions
fined as one that monitors a physical, chemical or bio- on pharmaceutical waters.
logical property of a process, and the measurement is
followed by another measurement within seconds. This Excursions and real-time recovery
continuous measurement technology is based on a In addition to measurement and control, TOC sensors
constant flow of sample through the sensor and the are used to monitor deviations, sometimes rapid or
ability to measure the process change in a brief time intermittent, from a baseline measurement. These ex-
period. An excursion can be rapidly identified with this cursions are caused by the introduction or release of
type of TOC sensor. Fast identification allows an ­imme- contaminants into the purification process. It may be a
diate response and intervention to prevent non- brief disruption with duration of seconds or minutes
compliant water from being used in the production or caused by a valve opening and closing for example,
from reaching the UPW water storage tank. This rapid followed by a return to baseline reading. Alternatively,
response capability can result in significant cost sav- it may be a longer disruption which results in a long

20 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 term baseline drift or change such as an RO mem-
Total Organic Carbon
14
brane defect. It can also be normal cyclical behavior Input IPA 10 ppb
12
due to water consumption or sanitization cycles. For CF-TOC
TOC A
these types of excursions, rapid, continuous, and real- 10

time measurement technology is an invaluable tool for

8

TOC, ppb
TOC measurements.
6

When the disruption is brief or intermittent, a fast up-

4
date rate allows the excursion to be detected, whereas
a slow sample rate measurement is likely not to detect 2

the intermittent failure. If there is a significant baseline 0

0 10 20 30 40 50
shift, a slow sampling frequency measurement system
Time (min)
is similar in terms of its detectability to a continuous
Figure 1: IPA response curves. CF TOC vs TOC A.
measurement system. Both fast and slow technologies
will see the shift. In the case of a measurement tech-
nology where there is a combination of fast response to produce (out of a 10 hours day, this represents
time and continuous measurement, a close and rapid sampling of <0.014% of the time) means that the wa-
(real time) inspection of the process is possible. This ter is not being monitored >99.98 % of the time. Since
combination of speed and continuous measurements water production is a continuous purification and con-
provides an immediate opportunity for non-compliant sumption process, a water system can be enhanced
water to be directed to drain or recirculated, rather than by real-time detection and analysis.
inadvertently used for product contact directly or indi-
rectly, such as a cleaning/rinsing process. When an excursion occurs, it is essential to relate the
accuracy of a TOC sensor to its ability to respond and
In a series of real-time recovery tests, three conductiv- identify the upset condition in a timely manner. Directly
ity based TOC systems (CF-TOC, TOC A and TOC B) stated, if the duty cycle of the measurement system is
were compared by performing testing on select typical low, the ability to detect an event is low. If the duty cy-
organic chemicals. All chemicals were prepared at cle is high, the ability to detect is high. Unless an event
concentrations of 10 ppb carbon. High purity water is being monitored, it will not be detected.
(TOC <5 ppb) was flushed through each analyzer for
30 minutes. An organic solution was pumped into If the excursion duration is regarded as an integration
each of the units for 5 minutes and the TOC data ob- window over which we determine the response factor
served for up to 1 hour to track the response. The del- from a TOC sensor, a sensor with continuous mea-
ay from a common manifold was calculated to be 21 surement technology would respond immediately and
± 5 seconds for all systems tested. The continuous be more accurate because the response is within the
flow TOC technology (CF-TOC) and two other technolo- time that the excursion was occurring. Conversely, if
gies were evaluated under these test conditions. a sensor’s main response is after the upset condition
due to a slow response time, then its integrated error
A test was performed with 10ppb TOC 2-propanol is higher, and it exhibits a greater response error.
(isopropyl alcohol or IPA). The CF-TOC sensor re- 16
sponds in less than a minute of the injection time to
14 Input IPA 10 ppb
IPA with a proportional response (Figure 1). By com- CF-TOC
TOC B
parison, TOC A responds similarly, but 5 minutes after 12

the beginning of the excursion. In a similar test (Figure 10

2), TOC B responds proportionally to the TOC distur-

TOC, ppb

8
bance, but 8 minutes after the IPA is injected. Again, in
both cases (Figure 1 and 2), the 5 minute excursion is 6

over before TOC A and TOC B detect it. The CF-TOC 4

technology responds to the excursion within 2 minutes 2

after its appearance, and it also detects the disappear-
0
ance of the excursion in real time. When discrete batch 0 10 20 30 40 50
Time (min)
measurements in the laboratory were more common,
sampling 1 liter of water which took about 5 seconds Figure 2: IPA response curves. CF TOC vs TOC B.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
21
 A real-time recovery error would incorporate both graphs, the total recovery error is dependent on the
Total Organic Carbon
speed of response and the percentage recovery or organic compound and the sensor being used. The
sensor response. Then the definition of the real-time bar graphs represent the total recovery error for a TOC
error would be: measurement system grouped by organic compound.
The lower the bar graph value, the closer that sensor
responded to a perfect response for the organic com-
pound injected. The varying errors show that none of
the sensors responded perfectly for all tested organic
compounds. Where NR is shown, this indicates that
Where I(t) is the input disturbance at time t, R(t) would there was No Response or a less than 1ppb shift from
be the sensor measurement in response to I(t) at time the baseline was observed during the measurement.
t, and Abs is the absolute value. A perfect response
would be when R(t) = I(t) at all times because the re- Each instrument has a variable real-time recovery error
sponse is instantaneous and equivalent to the dis- depending on the organic compound injected. Each of
turbance. The total recovery error for a perfect sensor these compounds represents one of thousands that
would then be the sum of all the real-time recovery may be present in a water purification system that
errors and would be equivalent to zero, i.e. makes up the TOC measurement.

In real water systems, both speed of response to an

excursion as well as recovery of response back to nor-
mal conditions are important in real-time monitoring. A
In actuality, these equations are relative errors as they TOC measuring system needs to respond rapidly to an
are calculated as deviations from a baseline response excursion and then just as quickly recover when the
which can vary from one type of sensor to the other. excursion has passed.

If the total recovery error for all the tested sensors was Conclusion
calculated for IPA using data collected from response A Real Time Release, continuous flow TOC sensor
curves in Figures 1 and 2, the plot in Figure 3 would ­provides rapid response to an excursion with an op-
be the result. Figure 3 shows that the longer the delay portunity in real time to respond to and divert conta-
in the response from the TOC sensor after an excur- minated water. This reduces downtime associated with
sion, the greater the accumulated error. The total error excursions, maximizes efficiency, and reduces cost
for the CF-TOC is lower because of the accuracy and associated with product loss, manpower, and equip-
the response within 2 minutes of the beginning of the ment. In brief, it allows closer control of the entire wa-
disturbance. ter purification process through the understanding of
the UPW system characteristics. It ensures that end
Figure 4 shows the final value of the total recovery users are receiving reliable good quality water for the
error at the end of the experiment. As shown in the bar various uses in production.

25000 100

90
CF-TOC CF-TOC
TOC A TOC A
20000 80
TOC B TOC B
Total Recovery Error [x(1.67 x 10-3)]

70
Total Recovery Error (%)

15000 60

50

10000 40

30

5000 20

10

NR NR
0 0
0 10 20 30 40 50 Urea MeOH IPA Sucrose Chloroform
Time (min) Time (min)

Figure 3. Total error accumulated over time Figure 4. Summary of Total Recovery Error – NR is no response

22 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 The Value of Measuring TOC
Total Organic Carbon

in CIP and Cleaning Validation Applications

In pharmaceutical manufacturing, process vessels, fer-

mentation tanks, process piping, medicine packaging
machines, and other equipment that comes in contact
with the product must have a user-defined and validated
cleaning method. Thorough cleaning is required to avoid
cross contamination between product batches as well as
preventing microbial buildup on vessel walls and equip-
ment. Examples of cleaning are WFI rinse or
Steam-in-Place. Clean-in-Place frequently employed for
process vessels, typically uses an acid followed by a
caustic rinse. A final rinse(s) with WFI ensures that all
chemicals used to clean the vessel have been removed
and that the vessel can be put back on-line for produc-
tion. In all cases where a WFI or PW rinse is part of the
cleaning process, the vessel or equipment can be con- Meeting TOC and conductivity instrumentation
sidered “clean” when the TOC and conductivity of the ­requirements for cleaning processes
water flushing out to drain is the same as that of incom- Appropriate cleaning methods and validation pro-
ing water. [Note - Any retention of residue or biofilm on cesses are defined by individual pharmaceutical users
the vessel walls is not included in this a­ nalysis.] for their specific equipment and in accordance with
internal Good Manufacturing Practice. However, be-
The current trend for the control of cleaning applications cause the WFI or PW waters used in CIP and cleaning
is to flush the final WFI or PW rinse for a pre-determined applications come in contact with process equipment
amount of time, monitoring conductivity until a specified and process vessels, these waters must meet USP
water quality is reached. Once the water quality has standards for TOC and conductivity measurements.
improved sufficiently, grab samples of the final rinse
product are taken for lab or batch analysis of TOC con- These TOC standards include a limit of detection of 0.05
centration or other analysis such as High Performance mg carbon/L (50 ppb), the ability to calibrate the sensor,
Liquid Chromatography (HPLC). This time-consuming and that the sensor meets a System Suitability Test (SST).
procedure not only causes significant downtime of This SST challenges the TOC sensor with two standard
equipment, it also may introduce sample contamina- solutions [500 ppb sucrose and 500 ppb p-benzoqui-
tion. Continuous on-line monitoring of TOC and none] and requires that the response efficiency of these
conductivity in real time during the final rinse phase of standards, adjusted for the TOC of the water used to
the cleaning cycle, rather than grab or batch sample make these solutions, be between 85% and 115%.
analysis, is an enhanced strategy for monitoring the
cleaning process of the final rinse cycle. The ability to quickly and easily perform the calibration
and SST in-house is an important feature of any TOC
By continuously monitoring the TOC and conductivity sensor used in CIP and cleaning processes, as it can
quality of the final rinse water, better control of the pro- further reduce costly equipment downtime as well as
cess can be maintained, saving both time and water. allow closer control of internal validation practices. In
The METTLER TOLEDO Thornton family of TOC and instances where low or no flow to the TOC sensor exists
conductivity sensors provides continuous, on-line, due to gravity drainage of the process vessel or other
real-time monitoring, ensuring that the CIP or cleaning restrictions, the accessory METTLER TOLEDO Thornton
cycle is determined by water quality and not a pre-set Pump Module can be used in conjunction with the
time or number of rinse cycles, which may result in METTLER TOLEDO Thornton 4000TOCe and 6000TOCi
prolonged wasted cycles or improper and incomplete families, providing constant delivery of the water sample
cleaning, and therefore non-compliance. to the sensor for accurate monitoring.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
23
 Real-time TOC Analysis Case
Total Organic Carbon

Safeguards Water Purity Study

To prevent bacterial growth, pharmaceutical-grade water systems require precise monitor-

ing and control of TOC. A European producer of pure water systems trusts in-line METTLER
TOLEDO Thornton instrumentation for ensuring customers of consistent water quality.

USF Water Purification GmbH designs, manufactures,

and maintains reverse osmosis and continuous electri-
cal deionization Purified Water and Highly Purified
Water treatment systems. The company serves phar-
maceutical industry customers throughout Austria and
Eastern Europe. The team has its roots in the early
1990s (at one time the team was part of US Filter,
which was acquired by Vivendi and subsequently by
Siemens Water). USF produces systems which sanitize
using hot water at 80 °C employing a fully automated
process. The company offers instrument calibration trol in PW and Water for Injection. The advent of USP
service and maintenance programs as a convenience < 645 > Water Conductivity and USP < 643 > Total
for its customers, which include Actavis, Teva, Pfizer, Organic Carbon introduced test methods that could be
Novartis, Boehringer Ingelheim, Baxter, Fresenius, used for equipment verification, on-line process con-
Ebewe and GL Pharma. trol, and release of water to production for the first time
in the pharmaceutical industry. In addition, the USP
In-line process monitoring offers real-time analysis specifications set regulations for the measuring instru-
METTLER TOLEDO Thornton measurement systems have mentation used for TOC and conductivity
been specified by USF engineers for nearly two decades. measurements such as system suitability, limit of de-
The innovative features, technical capabilities and robust tection, instrument resolution, and calibration require-
solutions of Thornton products have helped USF to ments for sensors and transmitters. Concurrently, all
develop and preserve a long standing reputation for of the USP wet chemistry tests for bulk waters were
providing high quality water systems to leading pharma- deleted, with the exception of microorganisms and
ceutical companies in the European marketplace. endotoxins (for WFI only). The EP TOC test, listed as
2.2.44, is identical to USP < 643 > in terms of limits
The Thornton 6000TOCi Sensor, in combination with a and methods. Subsequent updates to global pharma-
multi-channel, multi-parameter transmitter, is a high- copeias have continued to emphasize TOC and con-
performance system for determination of TOC levels in ductivity measurements for regulatory oversight.
pharmaceutical-grade water, while satisfying require-
ments of international pharmaceutical regulations. The Why use TOC sensors for the PAT initiative?
Thornton sensor provides accurate TOC measurement TOC sensors are used to quantify the concentration of
and response in less than a minute. Managing organic impurities in water. To ensure water quality
Director, Walter Lintner stated, “Alternative batch-style and water purification system performance, constant
systems require significantly more time to generate a monitoring is critical to allow action to be taken in a
response, which may result in lost production in cases timely manner, especially in the case of organic e­ x-
of serious TOC contamination.” cursions. It is this approach that is embodied in the
FDA’s Process Analytical Technology initiative. The PAT
TOC testing is required by the USP and EP initiative promotes the use of real-time measurements
In 1996, in USP 23 Supplement 5, conductivity and with the objective of ensuring good product quality.
TOC measurements were officially recognized as the This allows Real Time Release of product and leads to
best means to ensure ionic and organic impurity con- a more efficient operation. In cases where a TOC

24 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 instrument will be used for the USP / EP-relevant TOC tion systems typically show TOC levels down to 5 ppb
Total Organic Carbon
measurements in PW or WFI, the selected technology in the product water. Low TOC levels do not support
should comply with the current monographs in USP < growth of bacteria, thus yielding better control for our
643 > and / or EP 2.2.44. (See “Improving Water pharmaceutical customers.”
System Performance – Continuous Real-Time TOC
Measurements”). METTLER TOLEDO Thornton TOC sensor and monitoring
systems are ro-bust and easy to maintain. Mr. Lintner
Service and support are paramount continues, “One of the positive aspects of Thornton
From the point of view of price, performance, and ease instruments is the software – it is straightforward to use
of use, Mr. Lintner states that a Thornton TOC Sensor and allows us to calibrate quickly and efficiently. We
and multi-parameter transmitter is “the system of use Thornton instruments because the product, value,
choice for on-line measurement of TOC. Our purifica- and applications support all benefit the c­ ustomer.”

6000TOCi ISM TOC sensor

M800 transmitter

Pharmaceutical Industry
METTLER TOLEDO Best Practice
25
 Real-time Microbial Monitoring
Microbial

for Pharmaceutical Water Systems

Maintaining the quality of Purified Water and Water for a single point may only be tested a few times in a
Injection is vital in the pharmaceutical industry. On-line month. This can make identification and remediation
analytics play a major role in real-time chemical moni- of local microbial issues very challenging. This is
toring of water conductivity and total organic carbon. compounded by the fact that when a sample is col-
However, due to a lack of such on-line, real-time instru- lected for testing, it represents only a small volume of
mentation for the detection of microbial contamination, the water system or point-of-use at that specific time.
this vital measurement has been dominated by labora-
tory culture-based methods. These compendial testing Pharmacopeia guidelines
methods produce results on microbial water quality The FDA’s Process Analytical Technology initiative,
5 - 7 days after sampling. This situation causes great USP <1223> Validation of Alternative Microbiologi-
frustration as on-line conductivity and TOC sensors cal Method general chapter and the EMA’s (European
allow real-time release of pharmaceutical waters, but Medicines Agency) Guidance on Real Time Release, all
release is still delayed because bioburden excursions support the development and utilization of real-time,
cannot be identified in the same time frame. on-line microbial detection.

The Pharmaceutical industry is also challenged with The General Information Chapter USP <1231> Water
Point-of-Use testing for the distribution loop and for Pharmaceutical Purposes, has long supported on-
multiple points-of-use. A high percentage (industry line, continuous monitoring of pharmaceutical waters
estimates 80%) of the “positive” results from point-of- that allows historical in-process data to be recorded to
use microbial tests are actually false-positive because ensure the water system is in control and continues to
of sampling error or sample contamination from the produce water of acceptable quality.
technician or sample container or environment. Inves-
tigating these false-positives is time consuming and In USP <1231> compendial limits of 100 cfu/mL for
expensive, with some industry estimates putting the Purified Water and 10 cfu/100 mL for Water for Injec-
cost per event between USD 5,000 and 18,000. tion (WFI) are the traditional microbial requirements for
water quality. However, “water sampling protocols are
Due to the high number of points-of-use in a produc- limited in their ability to identify changes in ongoing
tion facility and the time involved in plate counting, water system performance making it difficult to provide

26 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 ongoing trend analysis, as ‘grab’ samples can only On-line measurement of microbial contamination
Microbial
provide a snapshot of the dynamic water system.” 1 Real-time microbial measurement methods accelerate
microbial detection and even improve microbiologi-
General Chapter <1223> Validation of Alternative cal quality control of Pharmaceutical Water Systems.
Methods encourages selection, evaluation and use The improved testing and speed of response allows
of on-line technologies as alternatives to compendial pharmaceutical products to reach the market faster. It
methods. Chapter <1223> provides guidance and also improves the understanding of the water purifica-
methods for the specification, qualification and imple- tion process. Real-time microbial detection permits a
mentation of alternative methods. true understanding of the actual bioburden profile in
the water loop and provides the ability to react to an
“Alternative methods and/or procedures may be used out-of-specification event in a timely manner.
if they provide advantages in terms of accuracy, sensi-
tivity, precision, selectivity, or adaptability to automa- Real-time water system surveillance increases pro-
tion or computerized data reduction, or in other special cess understanding, ensuring water system control
circumstances.” USP <1223> and increasing product safety. Microbial quality is
known prior to water release so that the user can
The USP <1223> and the EP (5.1.6) are informational react immediately to out-of-specification trends,
documents for the validation of alternative microbiologi- reducing regulatory risk and financial losses. By en-
cal methods, which detail validation procedures for abling reduced sampling and lab-based testing, human
different technologies and procedures. In addition, the contamination of grab samples is uncommon, thus
FDA and the EMA have also published guidelines for the reducing false positive investigations. Continuous
deployment of alternative microbiological methods. process trending also provides the opportunity to
reduce sanitization frequency, lowering costs and miti-
These initiatives and the pharmaceutical industry’s rec-
gating wear and tear on water system components.
ognition of a need for increased, real-time monitoring
of pure pharmaceutical waters led to the development
of instrumentation that allows life science companies
1) Novel Concept for Online Water Bioburden Analysis: Key Consid-
to rely less on time-consuming, culture-based lab erations Applications and Business Benefits
measurements of microbes. American Pharmaceuticals Review, July 2013

Pharmaceutical Industry
METTLER TOLEDO Best Practice
27
 Five Process Control Advantages
Microbial

of On-line Microbial Detection

1. Real-time data allows for full visibility of This limits the ability to understand when sanitiza-
excursions tion is needed on a water system. With real-time
Plate counting, the traditional method of bioburden measurement, facility personnel can use continuous
measurement, provides an estimation of microorgan- trending data to analyze baseline shifts before and
isms present more than five days after a sample is after sanitization. This also allows optimization of
taken. In contrast, by combining the techniques of sanitization frequency by determining if a sanitiza-
laser induced fluorescence and Mie scattering, it is tion cycle is needed due to a measured increase in
possible to continuously count the microorganisms bioburden in a water system. By optimizing saniti-
present in a water system in terms of Auto Fluores- zation frequency, a facility can reduce sanitization
cent Units (AFUs). Using this method, personnel can costs and decrease the wear on certain components
observe changes and excursions in their water sys- of their water system.
tem in real-time.
4. Determine sanitization effectiveness
2. React immediately to contamination Duration of sanitization cycles are also based on his-
Traditionally, microbial investigations and recall of torical information, often delaying water production
water are reactions to plate counting results that are and release for longer than necessary. For example,
unable to provide excursion details, including tim- a facility may use a standard of six hours of sanitiza-
ing and severity of contamination. Action may not tion when, in reality, sanitization is sufficient after
be taken for several days after an excursion has four hours.
occurred. However, with continuous AFU data, trend
information can be used proactively to reduce and Using real-time data and an established baseline, a
mitigate the risk of releasing contaminated water. facility can monitor changes in AFU count when heat
Once a facility has established a baseline or aver- sanitization occurs. With this process transparency,
age AFU level during normal operation, a user can a user can observe an increase in AFU counts and an
analyze how water system dynamics can impact the upward trend, indicating that sanitization is remov-
amount of microorganisms in the water system. ing the bioburden and biofilm that has built up in the
system. As sanitization continues, the AFU trend will
This results in greater process transparency and a come back down to its established baseline. This
better understanding of how changes to the water monitoring of the increase then decline of the AFU
system such as hydraulic events, fluctuations in data allows personnel to be confident in sanitization
demand, maintenance, and so on can impact the risk cycle effectiveness.
of contamination.
5. Increased productivity and faster water release
3. Optimize sanitization frequency When relying on laboratory-based bioburden mea-
Sanitization of a water system can be costly, can surements, water quality and risk level can be
increase wear on certain components, and limits the uncertain. Using at-line measurement that provides
time water can be produced or released. Typically, real-time data, the baseline for a water system is
sanitization frequency is based on historical informa- always available for optimization of sanitization
tion related to water system control across a multi- frequency and management of the rinse cycle after
tude of parameters that provide continuous on-line sanitization. With the ability to see the data trending
results, such as TOC and conductivity. down and the AFU count returning to the baseline,
personnel can determine when they are no longer at
With the traditional plate counting method of risk. Production is positively impacted by the abil-
laboratory-based bioburden measurements, only ity to release water sooner because the operator is
a snapshot of water system contamination is pro- confident that rinse time was sufficient and that the
vided five or more days after the sample is taken. water system is in control.

28 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 On-line Microbial Instrumentation Case
Microbial

for Real-time Monitoring and Control Study

For pharmaceutical manufacturers, on-line measurement provides process control and

real-time monitoring of their water quality. A leading biotechnology company improved
their processes with Thornton’s on-line 7000RMS™ Microbial Detection Analyzer.

Conductivity and Total Organic Carbon (TOC) are two

compendial process analytic parameters where on-
line/at-line measurements have been the accepted
standard for decades. However, when it comes to
monitoring for microbial contamination in WFI or PW,
the market has relied on laboratory-based methods
developed over a century ago. The pharmaceutical
industry, the pharmacopeias and regulators acknowl-
edge, recognize and endorse the need for the ability
to monitor bioburden contamination in real-time.
Integrating at-line bioburden measurement offers sig-
nificant advantages in process control.

The FDA and EMA are strongly promoting the Process

Analytical Technology (PAT) initiative to encourage
the use of on-line instrumentation for real-time pro-
cess control. The recent European change in method
of production for WFI has further emphasized the use
of real-time process analytics.

On-line/at-line microbial systems with continuous

monitoring are now being utilized by the pharmaceu-
tical industry to bring process control to this com-
pendial parameter. Utilization of real-time microbial
detection has multiple advantages for the industry
including real-time detection of bioburden, increased of four months. Using the 7000RMS, the customer
productivity, reduced use of rinse water and optimi- observed stable Auto Fluorescent Unit (AFU) readings
zation of sanitization. during normal operation and increased AFU counts
during sanitization cycles. In the first 30 days of the
Improved process efficiency with continuous data evaluation, the company established AFU baseline,
A leading biotechnology company evaluated the alert and action limits for their system.
7000RMS as a process monitoring tool in conjunc-
tion with plate counts as part of an overall control Understanding sanitization frequency and duration
strategy to facilitate rapid response to deterioration of The company’s Standard Operating Procedure (SOP)
their Utility water system. required a weekly heat sanitization from 00:30 am to
10:00 am. Before and during this process the com-
The 7000RMS analyzer was installed on an ambient, pany implemented the 7000RMS to monitor real-time
GMP WFI loop downstream from the return port under trend data that was used to evaluate the sanitization
temporary change control. Data was captured on the effectiveness and duration. There was no change
Building Control System during an evaluation period in the AFU baseline data prior to the sanitization,

Pharmaceutical Industry
METTLER TOLEDO Best Practice
29
Microbial

Figure 1: AFU trending data during sanitization and rinse. Dotted line indicates original rinse time.

suggesting that the interval between sanitization Real-time monitoring improves processes
cycles could be increased. This process change This biotechnology company identified several benefits
would result in reduced sanitization costs and pre- of implementing the 7000RMS in their water system.
vent premature replacement of worn water system Optimizing sanitization frequency and rinse duration
components. In addition, the company observed would reduce energy costs. Labor costs could also
the AFU baseline recovery after each sanitization, be reduced as a result of less sampling and labora-
which indicated the sanitization effectiveness. Using tory based testing, and fewer critical sample sites and
this trend data, the company had the opportunity investigations. Real-time monitoring could also lead
to optimize their sanitization cycles, thus reducing to faster remediation response to process parameters
downtime and increasing overall productivity. that reached action or alert levels, as well as increased
process understanding and product safety.
Optimizing system rinse time
The ability to review real-time trending data also Increased control, minimized risk
made it possible for the customer to reduce rinse In addition to making their processes more efficient,
time after sanitization. According to the customer’s the trending data provided by the 7000RMS also
SOP, a six hour rinse time was required. With the allowed the customer to better understand their water
7000RMS and an established AFU baseline, they system dynamics. With a more complete understand-
interpreted the trending data to conclude that the ing of how normal system events impact the microbial
AFU counts were within acceptable limits after only and biofilm environment, an out-of-specification event
four hours of rinsing (Figure 1). This provided the becomes easier to recognize. Critical decisions can be
potential to significantly reduce their rinse time and made based on real-time results, reducing the risk of
release water two hours sooner, resulting in more releasing contaminated water.
production time.

30 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Ensuring the Absence of Ionic Impurities
Conductivity

with Conductivity/Resistivity Measurements

The measurement of water’s electrical conductivity, or Conductivity sensors are also employed in TOC mea-
resistivity, can provide an assessment of total ionic surements where they are used to quantify the change
concentration (the presence of impurities) and hence of non-ionic organic compounds to conductive species
its suitability for use in pharmaceuticals manufacture. following exposure to deep ultraviolet light.

The most common method of measuring low-level Conductivity testing is required for USP Purified Water,
ionic impurities in ultrapure water systems is on-line Water for Injection, Water for Hemodialysis, and Pure
instrumentation. This technique is industry-tested in Steam Condensate.
the identification of trace ionic contaminants, where
the addition of 1 ppb of NaCl increases the conductiv- Effective July 1, 2004, the European Pharmacopoeia
ity of water from 0.055 to 0.057 µS/cm at 25 °C. This revised its conductivity requirements for the EP mono-
difference is readily measurable with today’s instru- graphs for WFI and Highly Purified Water. These waters
mentation. The measurement of water’s electrical con- have the same conductivity limit test required for USP
ductivity is described in microsiemens/cm (µS/cm) Purified Water, WFI, Water for Hemodialysis and Pure
and is measured by a conductivity meter and sensor. Steam. This test requirement is harmonized with USP
Resistivity is described in megaohm-cm (MΩ-cm), and <645> Water Conductivity test.
is the inverse of conductivity.

UniCond 2-electrode conductivity sensor with ISM

Pharmaceutical Industry
METTLER TOLEDO Best Practice
31
 Calibration Solutions
Conductivity

for Pharmaceutical Waters

METTLER TOLEDO Thornton has developed simple

analytical calibrators for use with the respective
UniCond sensors and M300 Analog transmitter firm-
ware to easily demonstrate that the conductivity and
temperature measurement circuitry complies with the
electronics accuracy specification of USP <645>
Water Conductivity as well as global pharmacopeia
requirements.
Pharma Waters Verifier
Pharma Waters Calibrators
Conductivity Calibrators are used to adjust the elec- Pharma Waters Verifiers confirm the accuracy of the
tronic measurement circuit located in either a trans- electronics at specific points within USP <645>
mitter or a sensor to comply with the electronics accu- guidelines.
racy specifications. Calibration is used to check,
adjust, or standardize a measuring instrument, usually Thornton Calibrators and Verifiers:
by comparing it with an accepted standard. Periodic • Easy to use unit provides confirmation of the
conductivity calibration is required to meet global conductivity and temperature accuracy require-
pharmacopeia regulations. ments of the measurement electronics to meet
USP <645> Water Conductivity
• Simple menu driven transmitter interface walks
the user through the verification process
• Accurate to ± 0.1µS/cm; ± 2°C
• Includes NIST traceable resistors for global
acceptance
• Compliant to USP, EP, JP, ChP, IP, other interna-
tional pharmacopeias
• Available for use with the Thornton M800
and M300ISM for UniCond sensors and
M300 analog transmitters for analog sen-
sors. Applications
Conductivity Calibrator • Required for compendial pharmaceutical water
applications to demonstrate compliance with
Pharma Waters Verifiers instrument requirements of USP <645> and
Pharma Waters Verifiers are uniquely designed tools global water conductivity regulations
which validate the accurate measurement display at • Recommended for all low conductivity pharma-
the transmitter and provide verification of communica- ceutical water applications <5 μS/cm.
tions between the end of the cable and the transmitter.

32 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Clean-in-Place Systems Manufacturer Case
Conductivity

Relies on METTLER TOLEDO Study

In-line conductivity measurement technology plays an essential role in the efficient

operation of Clean-in-Place systems, ensuring the highest possible levels of cleanliness
as well as optimal control over the cleaning solutions. A leading manufacturer of CIP
systems has selected Thornton conductivity instrumentation for
their performance and reliability.

Suncombe Ltd is one of the UK’s leading mobile Clean-

in-Place systems manufacturers and hygienic process
engineers.

Established in 1961, they have a wealth of knowledge

in designing and manufacturing cleaning and hygienic
process technology for the biopharma, food, and other
hygiene critical industries. Suncombe’s products are
supplied to UK, European, and international compa-
nies who demand high quality, reliable CIP systems.

CIP application
The CIP cleaning procedure is a multistep process.
Wash solutions are prepared in storage tanks and
used in specific ’recipes’ to carry out the cleaning of
vessels, pipework, etc. A final rinse with pure water • Tri-Clamp® sensor connections
takes place at the end of the cycle. Control of various • Conductivity ranges from 0.01 uS/cm to
process stages such as start of dosing of alkaline or 500 mS/cm
acid, or rinsing with water is carried out effectively • Material certificates for wetted parts, including
using in-line conductivity measurement. The system USP <88> Class VI
detects the conductivity of the solutions and provides • Panel mount transmitters providing analog out-
outputs to the local process control system to manage puts for both temperature and conductivity
the CIP program. • Sanitary designed sensors

New mobile CIP system METTLER TOLEDO solution

When Suncombe launched its latest range of portable METTLER TOLEDO Thornton provided a conductivity
CIP systems, it required the highest standard of instru- system using the M300 dual-channel conductivity
mentation. Dave Adams, director at Suncombe said, transmitter. This allows two conductivity sensors to be
“Our CIP systems are designed to incorporate top qual- connected to the same transmitter. The M300 comes
ity equipment to ensure that they provide reliable re- in two convenient sizes, ¼ DIN specifically for panel
sults in every use. We selected METTLER TOLEDO mount applications and ½ DIN for field, post or wall
Thornton to provide conductivity instrumentation on mount applications.
our MobileCIP™ systems, as we use their products
extensively with excellent results. We view METTLER The system uses a Thornton 2-electrode conductivity
TOLEDO as an excellent strategic partner for our sys- sensor for final rinse control as well as a Thornton 4-
tems as they provide excellent service and support.” electrode conductivity sensor for cleaning agent con-
trol. Both of the sensors are hygienically designed and
Conductivity equipment expectations have Tri-Clamp process connections as well as 3.1 B
The conductivity instrumentation in mobile CIP sys- and Class VI material certificates to satisfy the require-
tems for pharmaceutical customers requires a number ments of the pharmaceutical industry.
of conditions including:

Pharmaceutical Industry
METTLER TOLEDO Best Practice
33
 Reliable, Cost-effective Sanitization
Ozone

the Power of Ozone

Sanitization of pharmaceutical water systems has his-

torically relied upon either chemical or thermal pro-
cesses. But today, ozone production systems are
being installed in an increasing number of water sys-
tems as an alternative sanitization method. Ozone
(O3), an unstable triatomic form of oxygen, is 2,500
times stronger as a disinfectant than chlorine. In addi-
tion, ozone reacts with organics to break them down
ultimately to CO2, thus removing color and odor, and
eliminating a food source that could encourage biofilm
growth. Ozone, when dosed at the proper concentra-
tion and monitored before and after the ozone destruc-
tion system, meets the pharmacopeia regulation for Ozone molecule
“no added substances” to the water.
In addition, pharmaceutical manufacturers are con-
The increased use of ozone as a sanitization method cerned about the rising expenditure for regularly sani-
over the past decade can be attributed to a number of tizing a large pharmaceutical water system with heat
reasons including effectiveness in microbial and bio- or steam, and the consequent impact on their operat-
film control, and avoidance of harmful halogenated ing budget. As energy costs increase, the use of ozone
by-products, and cost efficiencies due to the low cost becomes more attractive, contributing to a trend that is
of ozone preparation and the zero cost of ozone remo- expected to continue.
val (compared to traditional chemicals).

34 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Application and Control of Ozone Sanitization
Ozone

for Pharmaceutical Waters

Ozone is a strongly oxidizing gas that is injected into

water or electrolytically generated in water. Dissolved
ozone converts back to oxygen in a matter of minutes,
depending on the temperature (chart below) and pH
of the water, so it must be generated on demand.
Ozone leaves virtually no harmful breakdown pro-
ducts, unlike chlorine and its related compounds
which can produce trihalomethanes and other car-
cinogenic compounds.

Liquid sanitizing chemicals or biocides such as hypo-

chlorite and related compounds are liquid/­liquid mix-
tures. Recent studies have demonstrated that biofilm
can be more hydrophobic than PTFE, preventing liquid
biocides from penetrating a bio-layer. Ozone, as a
powerful oxidizing dissolved gas, penetrates and de-
stroys biofilm to a much greater extent.

Dissolved ozone decay rate at pH 7:

Temp °C Half life
15 ~30 min
20 ~20 min
25 ~15 min
30 ~12 min

Ozone generation Ozone for disinfection in pharmaceutical water

Traditional ozone generators pass dry air or oxygen ­production
between high voltage electrodes where the corona dis- The sanitization of pharmaceutical water systems typi-
charge converts some of the oxygen to ozone. This is cally relies on heat/steam, traditional chemicals, or
the same phenomenon that occurs during a lightning ozone. Heated water systems must ensure that tem-
storm. The gas mixture is then contacted with the wa- perature is maintained adequately throughout the cir-
ter, either through a tank diffusion system or in a pipe culating water loop. Heating large volumes of water
with a venturi ejector. Intimate contact is made to max- and maintaining it throughout the system represents a
imize dissolution of the ozone. Excess air is vented large energy load. The heat lost by piping, even if in-
outside the system. sulated, puts an additional burden on plant air con-
ditioning systems. As a result, hot water systems are
Another ozone generation method is to electrolyze wa- known for their high energy consumption and utility
ter using a specialized catalyst to yield ozone as well costs.
as oxygen and hydrogen. The hydrogen is ven­ted out-
side the system and the ozone is generated and re- Traditional chemical treatments, while effective from a
leased directly into a side stream of the process water. microbial perspective, bear the burden of not only the

Pharmaceutical Industry
METTLER TOLEDO Best Practice
35
 chemical costs, but the costs of chemical removal and reached and maintained throughout the distribution
Ozone
the added downtime and risks to ensure that the system during the sanitization cycle. During this cycle
chemicals have been rinsed out of the water system. the water is not used for production. The ozone con-
centration maintained in the storage tank and the time
Ozone is recognized by the industry as an excellent and concentrations used for the sanitizing cycle are
alternative for disinfecting pharmaceutical, biotech, established for the individual system and its standard
and personal care products water systems. It com- operating procedures. The concentration could be as
plies with international pharmacopeias stating there low as 0.03 ppm for normal continuous operation to
can be “no added substances” since it will decay into as high as 0.35 ppm for the sanitization cycle.
oxygen under UV light. It is necessary to monitor for
ozone after the UV ozone-destruction lamps to ensure For a pure water system using ozone disinfection, the
the ozone has been fully removed before the water is ozone instrumentation plays a critical role for proper
distributed to points of use in production or lab areas. control of disinfection and periodic sanitization to help
achieve regulatory compliance.
Monitoring ozone
In a continuously ozonated system, on-line measure- Instrumentation for measurement and ­control of
ment and control of ozone are typically required. To ozone
achieve reliable sanitization of these water systems, Dissolved ozone instrumentation is available with a
ozone monitoring is required at three critical points range of capabilities and costs. For measurements
(see Figure 1). with excellent performance, high reliability, and ease of

Dissolved
Ozone
Sensor #3 Points of Use

M800
Multi-parameter,
Ozone Multi-channel
Generator Transmitter

Dissolved
Static Ozone
Mixer Sensor #2
Treated Water
Supply

Storage UV
Tank Dissolved
Ozone
Sensor #1

Figure 1: Ozone monitoring points

The first ozone measurement point (sensor #1) is after maintenance at reasonable cost, METTLER TOLEDO
the storage tank to ensure the proper concentration of Thornton offers dissolved ozone measurement with
ozone is maintained for effective disinfection. It also a choice of three multi-parameter instrument
provides the signal for controlling the ozonation rate platforms.
required from the ozone generator. The second mea-
surement point (sensor #2) is after the ozone destruct Individual measurements
system (254 nm UV light) to ensure the decomposition For basic pharmaceutical water applications, the
of the ozone before the water is distributed to produc- METTLER TOLEDO Thornton M300 analyzer/transmitter
tion points of use. The third measurement point provides one- or two-channels of measurement of dis-
(sensor #3) is utilized when sanitizing the entire distri- solved ozone and/or conductivity plus temperature in
bution loop. It is located at the end of the circulation any combination. This is a cost-effective choice where
loop to make certain that the required level of ozone is few measurement points are required.

36 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Multi-parameter measurements information, all within the sensor. ISM provides predic-
Ozone
To meet the requirement of many measurement points, tive maintenance tools with such capabilities as the
the METTLER TOLEDO Thornton M800 transmitter can continuously updated Dynamic Lifetime Indicator and
accept up to four analytical sensors in any combina- Time To Maintenance that can help avoid unneeded
tion of ozone, conductivity, and TOC. The latter two are maintenance time and expense with ozone and other
required by most international pharmacopeias. For sensors. ISM sensors can also be calibrated remotely
pharmaceutical water systems requiring three points of and then installed on-line with no extra effort.
ozone plus conductivity with temperature measure-
ments, these four-channel transmitters with up to eight Conclusion
analog outputs provide the ideal platform. In other Dissolved ozone is an effective sanitizer for pharma-
systems, the four analytical channels of the M800 can ceutical, biotech and personal care products water
also provide measurements of dissolved oxygen, pH systems. In order to ensure that concentrations or ab-
or ORP in any combination, plus two additional chan- sence of ozone meet requirements during the saniti-
nels for flow measurement. zation cycle as well as during normal operation, ozone
instrumentation plays a critical role for proper mea-
The M800 platform utilizes digital sensors with surement and control. METTLER TOLEDO Thornton
Intelligent Sensor Management (ISM®). ISM sensors offers reliable solutions for ozone measurement with a
include the complete measuring circuit and digital sig- range of especially convenient instrument platforms to
nal conversion within the sensor plus memory that re- match individual system requirements.
tains all sensor data, calibration, and diagnostics

M300 transmitter M800 transmitter

pureO3 dissolved ozone sensor

Pharmaceutical Industry
METTLER TOLEDO Best Practice
37
 Critical Ozone Measurement Case
Ozone

in Purified Water Systems Study

Ozone is a powerful disinfectant but also a strong oxidizing agent that can damage
pharmaceutical products. In purified water systems, ozone determination is vital
for purity assurance purposes. Christ Pharma & Life Science in Shanghai, China
chooses Thornton ozone sensors for their accuracy and durability.

Christ Pharma & Life Science GmbH, and Christ

Pharma & Life Science (Shanghai) Ltd. (formerly part
of the BWT Group), with operational centers in Europe
and Asia, offer a comprehensive spectrum of technolo-
gies for producing all grades of water required in R&D
and production environments in the pharmaceutical
and life sciences industries. In Shanghai, Christ
Pharma & Life Science has a manufacturing facility
where their LOOPO purified water storage and distribu-
tion system is produced. LOOPO maintains the quality
of Purified Water, Highly Purified Water and Water for
Injection right up to the point of use. The system has
passed both China’s GMP test and the relevant
European drug production tests.

Analytical performance is key tation plays a key role in Christ’s purified water sys-
In the LOOPO system, pharmaceutical purified water is tems, enabling their customers to achieve excellent
disinfected using ozone generated from the water itself, quality in their pharmaceutical products. According to
thus lowering the risk of external contamination result- Gu Lingna, Senior Project Manager at Christ Pharma &
ing from ozone produced from ambient air. As ozone is Life Science (Shanghai) Ltd, “The performance of the
a strong oxidizing agent that could be damaging to ozone sensor system has a direct bearing on the reli-
final products, the water is irradiated with UV light be- ability of the disinfection process, so it is of great
fore the first point of use to ensure all ozone is de- importance. The Thornton instrumentation operates
stroyed. Precise ozone measurement in the LOOPO stably and works consistently well.”
system is therefore very important, and the system
operators must be alerted to abnormal ozone values Ozone probe offers durability and
so that corrective measures can be taken. When points low-maintenance
of use are closed for a complete disinfection of the The main body of the probe is made of corrosion-
unit, the UV lamp is turned off and water with a high resistant stainless steel. A reinforced silicone mem-
ozone content is circulated through the whole system. brane offers high-level performance as well as the
The disinfection level is directly reflected by ozone durability required in the application environment. Gu
measurement. Ozone is determined at three positions Lingna reports that, “In actual use the ozone mem-
in the LOOPO distribution system: before the UV lamp, brane can have a lifetime of up to two years with
after the UV lamp, and in the loop return past the last regular maintenance.” The electrolyte in the probe must
point of use. be changed periodically, but this maintenance is very
simple and can be accomplished in a few minutes.
Important function of Thornton instruments After changing electrolyte or membrane, it is necessary
For ozone detection, Christ employs METTLER TOLEDO to polarize the probe in an ozonated sample for an
Thornton’s dissolved ozone sensor and compatible extended period. Where necessary, a single probe can
transmitter. Thornton high-quality analysis instrumen- test the ozone content of more than one sample. For

38 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 each sample, before the actual ozone reading is taken, and clear and simple interface, Christ Pharma & Life
Ozone
sufficient rinsing time is required to achieve a stable Science GmbH and Christ Pharma & Life Science
ozone value. (Shanghai) Ltd. have employed both on their various
systems to display ozone content.
Flexible measurement and monitoring of up to four
channels Dependable performance
Along with the ozone sensor, METTLER TOLEDO Since 1995, Christ has used an ozone generator on
Thornton offers a range of compatible analyzers. The over 300 of its pharmaceutical purified water systems.
Thornton M300 transmitter provides dual-channel Parts of these systems typically incorporate Thornton
measurements with the ability to monitor a combina- ozone sensors. “Experience has demonstrated that this
tion of ozone and conductivity sensors. The M800 probe is of consistently high quality and durability”,
model can accept up to four channels of ozone, TOC says Gu Lingna.
and conductivity sensors in any combination. Due to LOOPO is a registered trademark of Christ Pharma & Life Science
the transmitters’ convenient and flexible configuration, GmbH.

M300 transmitter pureO3 dissolved ozone sensor

Pharmaceutical Industry
METTLER TOLEDO Best Practice
39
 Data Integrity in Regulated Environments
Data Integrity

ALCOA+ for Pharmaceutical Waters

The completeness, consistency and accuracy of data is of ever-growing importance in

the pharmaceutical industry. The ALCOA+ framework is designed to ensure data from
equipment used in drug manufacturing is of the highest integrity. In respect to sensors
for pharmaceutical pure water systems, METTLER TOLEDO provides a tool to help your
water system be in compliance with the highest standards for electronic record keeping.

Introduction are considered to be trustworthy, reliable and equiva-

We live in a digital world, with access to a vast amount lent to paper records. The electronic signature and
of information that can be accessed from devices as record keeping requirements specified in 21 CFR Part
small as a cell phone. This is advantageous; we have 11 apply to all FDA-regulated industries, and therefore
instant access to the information we want, also, the cover records subject to the requirements set forth in
need for printed materials has been lessened. This reli- 21 CFR 210, 211 and 212.
ance on electronic data and records has had a pro-
found effect on scientific information, especially in The FDA guidance document released in 2016 –
regulated environments like pharmaceutical manufac- Data Integrity and Compliance With cGMP – intends
turing. Due to the fact that electronic records can be to clarify the current good manufacturing practice
altered or deleted, regulated environments such as (cGMP) regulations for drugs with regards to data
pharma/biotech must adhere to strict data integrity integrity. In this revised draft guidance, the FDA
regimes to prove that the data they submit to regulatory clarifies that “For the purpose of this guidance, data
agencies are complete, accurate, original, etc. integrity refers to the completeness, consistency and
accuracy of data“1. Therefore, the framework for this
21CFR Part 11 and ALCOA data integrity requirement is referred to by its acronym
Parts 210, 211 and 212 of Title 21 of the Code of ALCOA, which stands for Attributable, Legible, Con-
Federal Regulations (CFR) contain a number of refer- temporaneous, Original and Accurate. Table 1 gives
ences to data integrity. Many sections include more detail on the individual parts of this framework,
information regarding data integrity-related cGMP re- including some examples.
quirements for pharmaceutical drugs.
Additionally, the United States Pharmacopoeia (USP)
Other regulations that impact data integrity require- maintains the rules and guidance for water quality
ments include 21 CFR Part 11, the final rule on Elec- in the pharmaceutical and cosmetics manufactur-
tronic Records and Electronic Signatures, which was ing industries in the United States. USP <643> and
released by the FDA in 1997. This regulation defines USP <645> are two key regulations defining total
the criteria in which electronic records and signatures organic carbon (TOC) and conductivity limits for
water for injection (WFI) and purified water (PW).
These regulations, when coupled to the FDA‘s Process
Analytical Technologies (PAT) initiative, encourages
the pharmaceutical industry to use in-process control
of quality, rather than utilizing a final test for product
quality assurance.

ALCOA and ALCOA+

Beginning in 2019, The World Health Organization
(WHO) and other governing bodies requested an
update to ALCOA that establishes a more complete

40 Pharmaceutical Industry
METTLER TOLEDO Best Practice
Data Integrity
• Who generated the data?
Attributable • Who (if anyone) modified it?
• What system/instrument generated the data?
• Data must be readable/legible
Legible
• Electronic data must be ‘readable’ by humans
• Must be recorded at the time it was created
Contemporaneous • Cannot be transcribed later
• No Post-it notes, no notes on your hand
• All information must be in original format it was created in,
Original preserving accuracy, completeness, content and meaning
• Paper printouts are technically not ‘original’
• Recorded data needs to be accurate and second person verified (when appropri-
Accurate ate)
• Data in multiple locations need to agree with each other

Table 1: Details of ALCOA framework

definition of data integrity. The resulting framework, Additionally, the solution is based on well-known and
ALCOA+, includes additional elements that are now trusted METTLER TOLEDO instruments such as the
being implemented as recommended by WHO and 6000TOCi, UniCond® and pureO3™ sensors, combined
the International Committee on Harmonization (ICH). with the M800 transmitter. This provides very high
ALCOA+ adds the following four categories: Complete, confidence in measurement accuracy and water system
Consistent, Enduring and Available (Figure 1 and Table 2). control. The software on the transmitter and PC tool are
multi-language, allowing global organizations to imple-
A multi-parameter data integrity solution ment the solution anywhere.
In order to meet the requirements of ALCOA+ with
regard to electronic record keeping and data integrity for More importantly, the M800 transmitter does not store
pharmaceutical waters, METTLER TOLEDO Thornton has any electronic records or measurement data that could
developed the RecordLOC™ data integrity package. be accidentally manipulated, altered, changed or deleted,
therefore meeting the predicate rule requirements of 21
RecordLOC is a two-part system comprising a PC CFR Part 11 and ALCOA+. The M800 transmitter does
software tool and a METTLER TOLEDO M800 2-chan- provide the end-user with the ability to graphically view
nel, multi-parameter transmitter with 21 CFR Part 11 the measurement parameters over a preselected time
compatibility. The system can be configured with any period. However, the graphic representation itself is not
combination of two sensors including TOC, conductiv- stored or used for record keeping. For compliant digital
ity and/or dissolved ozone. RecordLOC provides a record keeping, the M800 transmits electronic
transmitter-stored, encrypted, audit trail; however, all
user data is stored on the PC to better comply with the
ALCOA+ requirement that data is legible, original and
contemporaneous.

RecordLOC is unique in that it provides a complete au-

dit trail of TOC as well as conductivity and/or dissolved
ozone sensors. This multi-parameter ability is superior
to a simple, single-parameter system because it allows
users to find and record simultaneous excursions in
TOC, conductivity or dissolved ozone, unlike similar
solutions that only record TOC and/or conductivity.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
41
Data Integrity
L C O
Legible Contemporaneous Original

A A
Attributable ALCOA+ Accurate

A C
Available E C Complete
Enduring Consistent

Figure 1: ALCOA+ Framework

Complete All recorded data require an audit trail to show nothing has changed
Consistent Data needs to be chronological (by date stamp)
Enduring Data must be available long after it was generated (decades)
Available Data must be accessible, normally achieved with electronic data

Table 2: Additional elements added to ALCOA for ALCOA+

data to a PLC, SCADA or Data Collection System (DCS) Conclusion

that meets 21 CFR Part 11 and EC GMP Annex 11 METTLER TOLEDO Thornton‘s RecordLOC data integrity
requirements. package, based on the M800 transmitter and well-
established sensors such as the 6000TOCi, UniCond
RecordLOC also helps users better comply with the FDA‘s or pureO3, offers an easy-to-use, audit-ready system to
“No added substances“ rule, by showing if an excursion help facilities become ALCOA+ compliant and conform
in dissolved ozone level has occurred during normal to the latest regulations for electronic records and
operation, which would violate Part 184 Subpart 1563 of reporting. This system helps eliminate paper records for
the CFR for addition of antimicrobial agents in water. water systems and complies with the fast-moving PAT
initiatives set by the FDA.
Figure 2 shows a partial audit trail format including
the configuration of the transmitter and displays the RecordLOC offers a robust, easy-to-implement, multi-
level of detail that RecordLOC brings to electronic parameter audit trail based on known technology
record keeping. that is truly global with full multilanguage support for
multinational organizations.

42 Pharmaceutical Industry
METTLER TOLEDO Best Practice
 Water system excursions are noted (time/date stamped)
Data Integrity
in audit trails for TOC, conductivity and/or dissolved
ozone and these records are encrypted (unmodifiable).
RecordLOC offers organizations peace-of-mind that their
water systems comply with the highest electronic record
keeping standards for TOC, conductivity and dissolved
ozone.

References
1:https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/part-11-electronic-records-
electronic-signatures-scope-and-application

Figure 2: Audit trail showing setup of the M800 transmitter.

Pharmaceutical Industry
METTLER TOLEDO Best Practice
43
 www.mt.com/pro
For more information

METTLER TOLEDO Group

Process Analytics Division
Local contact: www.mt.com/pro-MOs

Subject to technical changes

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ISM, UniCond, 7000RMS and pureO3 are trademarks of the METTLER TOLEDO Group.
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