Transcript Achieving USP Compliance for PW and WFI Waters

TOC and Conductivity
for
USP and EP Water Systems
Content
1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC
and Conductivity Analyzer
Dissociation and Conductivity
• Conductivity measures ionic activity
• Ionic compounds dissociate into ions, then re-associate back
into the compound
• E.g. Sodium Chloride (NaCl) made from Na+ and Cl• Add energy and the Na+ and Cl- split, or dissociate
• The ions then contribute to the conductivity of the water
• Some substances dissociate more readily and contribute more
strongly to conductivity
• Different temperature compensation curves for different waters
Conductivity
Conductivity Meter
Cl-
Na+
+
+
Measurement
Cell
Conductivity = TOC
Conductivity varies with temperature
Temperature
USP<645> Conductivity & Temperature
• Conductivity meters will report different results depending on:
• The compounds present in the water
• The temperature compensation curve selected
• Hence pharmacopoeias call for un-compensated, e.g. USP<645>:
Content
1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC
and Conductivity Analyzer
On-line TOC analysis – principle of operation
Conductivity Meter
-
+
+
Measurement
Cell
UV
lamp
On-line TOC analysis – principle of operation
Conductivity Meter
Organic material
turned to CO2
+
++
-- +
UV
UV
On-line TOC analysis - Principle of Operation
Conductivity
Organics oxidised to CO2
d conductivity = TOC
UV on
Time
Letter of the Law
USP (‘till recently) “… share the objective of completely oxidizing
the organic molecules in an aliquot of sample water to carbon
dioxide…”
EP states “… have in common the objective of completely
oxidizing the organic molecules in the sample water to produce
carbon dioxide…”
Only Hach’s, End Point Detection method, strictly meets this
requirement for online TOC analyzers
Dynamic End Point Detection
USP <643> Requirement: Instrument Must Completely Oxidize the Sample
Content
1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC
and Conductivity Analyzer
Validating the TOC analyser
1. Validate that the instrument matches the URS
2. Validate that installation is as per manufacturer
3. Verify Calibration
 TOC
 Conductivity
 Temperature sensor
4. System suitability
5. Verify connections to remote systems
6. Performance qualification
 Calibration is stable
 Analyser works correctly
Tests to validate the analyser
1. Validate that the instrument matches the URS
2. Validate that installation is as per manufacturer
3. Verify Calibration
 TOC
 Conductivity
 Temperature sensor
4. System suitability
5. Verify connections to remote systems
6. Performance qualification
 Calibration is stable
 Analyser works correctly
Validation documents & procedures
• Demonstrate URS requirements are met through,
Commissioning, IQ and OQ
• PQ demonstrates that the analyzer is stable and can support
required calibration and system suitability intervals
6 monthly
testing
Week 1
IQ, Commissioning
First 4 weeks
Calibration stability, System suitability
Tests to validate the analyser
1. Verify that the instrument matches the URS
2. Verify that installation is as per manufacturer
3. Verify Calibration
 TOC
 Conductivity
 Temperature sensor
4. System suitability
5. Verify connections to remote systems
6. Performance qualification
 Calibration is stable
 Analyser works correctly
1000
TOC Calibration – factory & on site
0
Reported TOC
Factory Calibration
0
Injected TOC
1000
TOC Calibration on site
TOC
750ppb
500ppb
250ppb
Water system TOC value – modern system = 30 to 70ppb
Certified traceable standards
Calibration – As Found, As Left
System Suitability Test Must Be
Performed
System Suitability is not calibration!
System suitability is “the process of validating whether your
system (i.e. TOC analyzer) is acceptable for providing useful
analytical data without any bias.”
This is typically done by:
• Analyzing a material that is easy-to-oxidize (sucrose)
• Analyzing a material that is difficult-to-oxidize (1,4 benzoquinone)
• Calculating the ratio of the responses
System suitability – USP<643> & EP2.2.44
System suitability calculation
Sucrose analysis result
= 475ppb TOC
Benzoquinone analysis result
= 485ppb TOC
Calculation
=
Sucrose
Benzoquinone
= 475 = >85%<115%
485
Verifying conductivity – USP<645>
1. Verify meter accuracy (+/- 0.1mS)
2. Verify cell constant (+/-2%)
3. Verify temperature sensor (compensation)
Temperature sensor verification
Verifying conductivity – meter
accuracy
Accuracy of
meter
Verifying conductivity – meter
accuracy
Disconnect
measurement cell
Verifying conductivity – meter
accuracy
Meter = Resistor +/-0.1mS
Replace cell with
NIST traceable
resistor
Verifying conductivity – cell
constant
Function area and distance
Area
Distance
Verifying conductivity – cell constant
•
Introduce certified conductivity standard
• +/-2% of certified standard
• Cell constant known within +/-2%
Content
1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC
and Conductivity Analyzer
PAT700 TOC Analyzer with OASIS
Onboard, Automated Standards Introduction System
TM
Introduction to the ANATEL
PAT700
• On-line TOC analysis with complete sample oxidation
• OASIS
TM
Onboard, Automated Standards Introduction System
• Calibration and system-suitability test SOP built-in via color
touch-screen
• Individual 4-20mA outputs for TOC, temperature and
conductivity
• Main and standby auto-switching UV lamps with UV Detect™
technology
• IP 56 stainless-steel enclosure improves protection
from water and particulates
PAT700 – Supports all test
requirements
• USP <643> Total Organic Carbon
• USP <645> Conductivity
• USP <788> Water for Injection
• USP <789> Opthalmic Water
• EP 2.2.38 Conductivity
• EP 2.2.44 Total Organic Carbon
• JP <60>
• 21 CFR Part 11
TM
OASIS Technology
Saves time and delivers improved confidence in quality
• All bottles for a test installed at once and tests automated
• Information about each standard stored in RFID tag on the bottle
– contents, concentration, certified value, lot number, expiration date
– (Manual data entry possible for customer prepared standards)
• Analyzer voids bottle following test
• OASIS can be used for grab sample analysis
Non-Hach Standards Warning Message
If the user selects “No”, then the test is cancelled and the user is
placed back at the Run Standards selection screen.
If the user selects “Yes”, then the user is prompted to enter all of
the bottle information manually and the test is allowed to
continue as if the bottle did not have an RFID tag at all.
PAT700 TOC Analyzer with OASIS
Grab-sample analysis
TM
Grab Sample Analysis
• Utilizes OASIS sample bay
• Up to 4 grab sample bottles at a
time
• Grab Sample Bottle ID nine
character alphanumeric
– (ex. PW POU 01 )
PAT700 TOC Analyzer with OASIS
OOS sample capture and root-cause
analysis support
TM
OOS sample capture capability
1. Utilizes OASIS sample bay
2. OOS triggers automatic collection of
two samples
3. Re-tests 1 bottle to confirm OOS
4. Saves one sample for analysis in
laboratory to support root-cause
analysis
PAT700 TOC Analyzer with OASIS
21 CFR data export
TM
21 CFR Part11 Data Export
TOC Dataview PC Software
Allows the viewing of encrypted data
Allows decrypted data to be saved
Encrypted file exported as filename.hef
Read-only .pdf for record retention
.txt files to load into LIMS database
PAT700 TOC Analyzer with OASIS
Clean-In-Place verification
TM
On-line Monitoring of CIP
Final Rinse Water Verification
Conductivity can be used for detecting acid wash residues
TOC can be used as broad-spectrum test to detect presence of
drug material residues
Unit programmed to meet user’s specific criteria
• Either conductivity threshold
• Or time based
After TOC analysis, reports results and return to idle mode
On-line Monitoring of CIP
Final Rinse Water Verification
• Automated Mode (plc controlled):
• Unit idle until called for
• TOC analysis triggered via:
• Digital input, or
• Serial command, or
• Modbus over Ethernet
• Reports results and return to idle mode
PAT700 TOC Analyzer with OASIS
Laboratory TOC analysis
TM
PAT700 with auto-sampler
• Autosampler for laboratory use can load up to 36 vials
• e.g. point-of-use and rinse water samples.(0-2000ppb)
• Provides a laboratory TOC analyzer without reagents or carrier gas
PAT700 TOC Analyzer with OASIS
Water loop monitoring and root-cause
analysis support
TM
Dual-stream option PAT700
Two inputs
• One on the PW/WFI loop start, one on the return
– Brackets loop quality
– Helps root-cause investigation to find contamination source,
e.g. feed-water or point-of-use
Bracketing POU for On-line Release
Contamination
Source
?
Points-Of-Use (POUs)
Contamination
Source
?
Pure Steam
Generation
Distillation - WFI
PAT700 TOC Analyzer with OASIS
12-month service and calibration
intervals
TM
UV DetectTM Diagnostics
• Direct measurement of UV source performance
– Diagnosis of UV status
– Fast, real-time lamp feedback
 On-line: Verified after every TOC analysis
 Off-line: Can be conducted in diagnostic
mode after lamp replacement
 Detects rouge contamination
• Provides confidence for on-line water release
– Standby UV lamp automatically switched on if
main lamp fails – avoids gaps in analysis data
• More reliable than simple “hours-of-operation”
counters
• Reduces cost-of-ownership – analyzer can
support 12-monthly calibration and service
intervals
Questions?
PAT700 TOC and Conductivity Analyzer