Transcript Monitoring Total Organic Carbon in Pharmaceutical High

TOC MEASUREMENT
OF PHARMA
WATERS
Sheesh Gulati
Monitoring Total Organic
Carbon in Pharmaceutical
High-Purity Water Systems
…How to Meet USP <643> and EP 2.2.44
TOC and USP <645> and EP 2.2.38
Conductivity Requirements
TOC -- HISTORY
• TOC analysis techniques were
developed back in the 1960s as a
means of better understanding the
contents of potable water and also
f a c t o r y w a s t e w a t e r .
• As these waters typically contained high
levels of TOC (up to 1,000PPM), the
analysis techniques were not suitable
f o r U l t r a P u r e Wa t e r.
• With advances in technology , newer,
more sophisticated methods of
measuring TOC were developed .
EVOLUTION OF TOC LIMITS
PHARMACEUTICAL GRADE WATER
USP Standard
TOC Limit ppb (1998)
Water for Injection
500
SEMICONDUCTOR GRADE WATER
SEMI Guidelines
1992
ppb TOC attainable
<1
ppb TOC acceptable
<2
ppb TOC alert
5
ppb TOC critical
19
Introduction and Background
• TOC is an acronym for total oxidisable carbon, more
commonly referred to as total organic carbon.
• Original laboratory TOC methods were developed to
help correlate Chemical Oxygen Demand (COD)
and Biological Oxygen Demand (BOD) in drinking
and waste waters.
• BOD test requires five days (5-day BOD) and
provides little information for detecting fast changes
or excursions of organics. Also the 5-day BOD test
is totally manual and no official on-line method is
available.
• The COD test uses significant amounts of
hazardous chemicals and mercury compounds.
TOC
Total organic carbon analysis is a
determination of organic carbon in a sample
regardless of its oxidation state or
biodegradability. Other measures of total
organic matter (e.g., COD, BOD) may
respond differently to solutions of equal
carbon concentration depending on the
oxygen content or the bidegradation kinetics.
Definition of Carbon in
Water
Sources of Total Organic
Carbon
• Organic carbon, especially at ppb levels, is pervasive
in water purification systems. It is a very dynamic
contaminant to measure, if not carefully controlled.
– Feedwater - municipal, surface, and/or wells influenced by
fertilizers, pesticides, vegetation, dumping of waste
– The High-Purity Treatment Process - ion exchange resins, RO
and filtration membranes, softeners, carbon beds, chemical
additions
– Distribution System - plumbing, pumps, valves, joints, fittings,
storage tanks, biofilms, use points
On Line & Off Line
TOC
• TOC can be measured both on- and off-line.
Off-line measurements (laboratory methods)
are typically used for high concentrations (>1
ppm). On-line measurements are typically used
for sub-ppm (<1000ppb) detection and quicker
response than the laboratory methods. Most
industries particularly pharmaceutical and
semiconductor manufacturing, now use on-line
measurements due to the faster response
which is required for process control.
ON-LINE vs.LAB TOC
• A debate has always existed concerning which is
better, on-line analysis or laboratory testing. Today,
many parameters that can affect the drug
manufacturing process are being measured on-line. It
is important to be able to develop trending information
for these parameters in order to determine that the
process is in control. On-line measurements can
provide real-time data without having to wait for
analytical results from the laboratory and help avoid
major upsets in the manufacturing process.
• As soon as you remove a high-purity water sample
from its environment, the sample is no longer
representative of the high-purity water in the
system.
On-line Methods
 Continuous data
 Real time data
 Trending information
 Low cost- ofownership
 No sample handling
 No sample
contamination
 Measure in own
environment
 data becomes
valuable information
for efficient operation
of a water system
Laboratory Methods
 infrequent results
 delayed data
 no trending
information
 high cost-ofownership
 sample tracking
protocols
 grab sample
contamination
 measure foreign
environments
ISSUE
Operating Personnel Required
Sampling Personnel Required
Auto Sampler Required
Computer required for Operation
PC required for Data Storage
Sample Containers required
Glassware Washers Required
Syringes Required
Oxidant required for operation
Acid required for operation
ON-LINE
LABORATORY UNITS
0
0
No
No
No
No
No
No
No
No
1
1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
ON-LINE vs. LABORATORY TOC ANALYSERS
Gas required for operation
Sample Time
Sampling Difficulty
Sample Purging Required
Transportation of sample required
Quality of Data
Measuring Purgeable Organics
Minimum Measurable Range
Weight
Size
Hot DI water
Networkable
No
Few Seconds
Automatic
No
No
High
Accurate
1 ppb
Under 8 lbs.
Compact
Yes
Yes
Yes
Several Minutes
Difficult
Yes
Yes
Low
Not accurate
4 ppb
100 lbs.
Large
No
No
ON-LINE vs. LAB TOC
Very similar to a movie with continuous
frames, an on- line analyser does not
miss a frame or a TOC excursion.
However, a laboratory method is like a
single frame (still) photograph that
takes a "snapshot" of the system.
With "snapshots", TOC excursions can
be measured wrongly or may be missed
completely.
TOC analysers Components
The two basic components of any TOC analyzer
are:
1. The Oxidation Reactor, which converts the
organic carbon in the water to CO2 gas, either by
thermal, chemical or ultraviolet radiation.
Oxidation efficiency, assuring complete conversion
of the organic carbon to CO2, is critical.
2. The CO2 Detector, which measures the
concentration of the CO2 gas generated in the
oxidation chamber. This component is critical for
precise analytical results, since it directly
correlates to the organic carbon content of the
analysed water.
BASIC TOC ANALYZER
The Oxidation Reactor
For ultra-pure water analysis, two
techniques are in common use:
• High Temperature Catalytic Oxidation
• UV Oxidation, with/without the
addition of chemical reagents
(persulphate)
High Temperature Oxidation
• This method uses a high temperature furnace into which
a water sample is injected . The furnace normally
contains a platinum or cobalt catalyst. The process
oxidises all the carbon materials to CO2, the quantity of
which is directly proportional to organics in the sample.
The actual measurement is of Total Carbon (TC)
• A later variation on this method is based on the use of
two furnaces. A sample of water is equally divided and
put into the furnace chambers, one at 150°C and the
other at 950°C. The lower temperature furnace
measures Organic Carbon (TIC), while the high
temperature furnace measures Total Carbon (TC). The
TOC can be calculated by subtracting the TIC value
from the TC value i.e. TOC=TC-TIC.
UV/Chemical Oxidation
• This method offers a low maintenance, high
sensitivity method but must demonstrate its
efficiency to fully oxidise the organic carbon to
CO2 in the particular application.
• To compensate for oxidation limitations of some
UV reactors, the addition of an oxidising reagent
(usually a persulphate) aids in the conversion of
the organic carbon to CO2 gas.
• Limitations of this method include inaccuracies
associated with the addition of any foreign
substance into the analyte. “Blanking” of chemical
additions help but still contribute error to the
analysis in levels below 50 ppb TOC.
DISADVANTAGES OF COMBUSTION &
PERSULPHATE METHODS
Each of the above mentioned methods
has requirements of acids, reagents and
gases. This adds to the complexity of
measurement and also requires the skill of
a trained person, normally a technician or
scientist. In most cases the water sample
must be removed from the DI plant, this
making it susceptible to contamination.
DISADVANTAGES OF COMBUSTION &
PERSULPHATE METHODS
Additional drawbacks of this technique are the
routine maintenance required and frequent
calibrations to maintain accurate results. With
rare exceptions the methods that employ
acidification and persulfate addition lose the
volatile organics which can be significant
contaminants in very low level TOC, high purity
water systems. In general, operating costs are
high especially as the reagents and gases have
a finite shelf-life
CO2 Detector
Two basic methods are in common use:
• CONDUCTIVITY
AND
• NON-DISPERSIVE INFRARED (NDIR)
• THE CONDUCTIVITY method measures the
conductivity of the sample before and after it is
oxidised, attributing this differential measurement
to the TOC of the sample. During the sample
oxidisation phase, CO2 (directly related to the TOC
in the sample) and other gases are formed.
Definition of
Pharmaceutical Water
• The exercise was to address compendial
waters: “any water intended for use in a final
dosage form.”
• Examples of compendial waters include:
–
–
–
–
–
–
–
–
Water for Injection(s) (WFI)
Bacteriostatic Water for Injection
Sterile Water for Inhalation
Sterile water for Injection
Sterile Water for Irrigation
Purified Water (PW)
Highly Purified Water (EP only)
Sterile Purified Water
Bulk Water
Packaged Water
USP <643> TOC Method
Requirements (1)
• Nominal TOC limit of 500 ppb as determined
by the Standard Solution results, or Limit
Response
• Instrument must completely oxidise the
sample
• Instrument detection limit of 50 ppb
• On-line or laboratory test
• Use a calibrated instrument
• Perform a System Suitability test on a
calibrated instrument with recovery levels of
85 -115%
USP <643> TOC Method
Requirements (2)
Defining the commonly used terms
in the <643> method:
• Standard Solution (500 ppb C by sucrose RS)
= rs
• Standard Solution or Limit Response = rs - rw
and establishes the PW & WFI pass/fail limit
• Reagent Control Water = rw
• System Suitability Solution
(500 ppb C by 1,4-benzoquinone RS) = rss
• System Suitability Solution response = rss - rw
• Response Efficiency = [(rss - rw ) / (rs - rw)] x
100
What is System Suitability?
• System suitability is not calibration!
• System suitability is “the process of validating
whether your system (i.e. TOC analyser) is
acceptable for providing useful analytical data
without any bias.”
• This is typically done by:
 analysing a material that is easy-to-oxidise
(sucrose)
 analysing a material that is difficult-tooxidise
(1,4 -benzoquinone)
 calculating the ratio of the responses
Frequency of System
Suitability
•
•
•
•
•
•
USP <643> specifies “periodically” and EP
2.2.44 specifies at “suitable intervals” ??
Water system dependent
Instrument dependent
Quality system and company protocol
dependent
Measure a validation check standard for
verification of calibration
Re-calibration suggests new system suitability
Frequency of system suitability should be
determined systematically, using historical data
Meeting the USP <645>
Conductivity Requirements
There are 3 basic requirements that
the conductivity equipment must
meet:
– “The conductivity cell constant… must be
known within ±2%.
– “The instrument must have a minimum
resolution of 0.1 µS/cm…”
– “…the instrument accuracy must be ±0.1
µS/cm.”
Conductivity/Resistivity
& Temperature Compensation
• Typically high-purity water is specified as
resistivity. M-cm = 1/µS/cm (temperature
compensated)
• Conductivity increases as a function of
temperature.
• Temperature compensation algorithms
calculate what the conductivity would be at 25
°C
• Pharmaceutical nomenclature is conductivity
and <645> is temperature uncompensated.
Common Locations for Online TOC Sensors
• Supply
– After the final purification component and prior to
distribution to the use points
• Return
– After the use points as the water is recirculating to a
storage tank
• Before and after any storage tank
• Before and after distillation
• Before and after deionization
• Before and after UV sterilizing or TOC destruct units
• After reverse osmosis
ON-LINE + OFF-LINE TOC
ANALYZER
Model DI 1000
ON-LINE + OFF-LINE TOC ANALYZER
Model DI 1000
DI 1000 TOC analyzer is a patented product, it can detect
total organic carbon (TOC) contained in the water, by
calculating it from total inorganic carbon (TIC) and total
carbon (TC). DI 1000 analyzer operation principle is to
oxidize microorganisms by UV lamp and convert organic
carbon into carbon dioxide. Then TOC analyzer adopts
direct conductance method to detect the concentration of
carbon dioxide and report. During testing procedure, TC
and TIC are detected and TOC is equal to TC- TIC (TOC
= TC-TIC)
MODEL DI 1000 TOC ANALYZER
•
•
•
•
•
•
•
•
•
FEATURES:
Low power consumption, no consumables.
Professional design for highly purified water test,
monitoring on line.
Memory of the last six months' records automatically,
able to look up the record for every day and print the
test results.
Test speed is fast and time of flushing piping is short.
Small, light, portable and easy to move.
Designed with buzzer alarm for upper limit.
Easy to test according to USP.
Large 320x234 color screen and personalized
interface.
RS232 digital interface and micro-printer interface.
MODEL DI 1000 SPECIFICATIONS
 Power supply: 220V, 50Hz, AC
 Rated output: 100W
 Dimension: 44cmx18cmx26cm
 Measuring limit: 0.001mg/L
 Measuring range: 0.001mg/L ~ 1.000mg/L,
also display in 1 to 1000 ppb
 Analysis time: 4min
• Sample temperature: 1-95 deg C
 Sample flow rate: 0.5ml/min
 Mini Printer included
 Heat exchanger included