monitoring disinfectants residuals in pharmaceutical water systems
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Monitoring Disinfectants Residuals in Pharmaceutical
Water Systems
Rich Bucha Support Manager Regional Sales Manager
Swan Analytical Instruments
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Introduction • The use of municipal (potable) water as make up water
source for pharmaceutical process • Further common treatments include reverse osmosis
(RO), IX, and either distillation, or ultrafiltration to ensure compliance with USP standards.
• Additionally the raw water will contain disinfectants
which must be removed at certain points in process • Prior removal of disinfectants such as chlorine
(treatment) and ozone (loop) in the pharmaceutical production process is necessary for PW and WFI
3
Introduction Continued
• Monitoring of the these individual processes is paramount to ensure the system is sanitary and as well as no residual chemicals are present in the final product.
• There are a few methods available to monitor these
process residuals 1. Amperometric 2. Colorimetric • Each method has its differences and suitable application
uses.
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USP Water Production Process • Municipal water will contain chlorine or chloramines after
which goes through a series of treatment processes in the pharmaceutical facility
• Such processes can include reverse osmosis(RO), ion
exchange, distillation(WFI), and UF • Chlorine must be removed in the treatment process to
protect RO membranes as well as not to be in the final product
• Ozone is used in the production process for sanitation of
water loops and storage tanks(biofilm). The benefit of ozone is that it’s a strong oxidant and it is also easily removed which is critical for PW and WFI
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USP Water Production Process • USP states Water For Injection (WFI) will contain "no
added substance". • FDA considers ozone to be an added substance
therefore it is necessary to be removed. • Purified Water, (water not intended for direct
transdermal injection) , is required to label ozone as an added ingredient or prove that the ozone has been removed from the water.
• Instrument(s) used to verify that ozone is no longer
present in either type of water must meet the strictest accuracy and low level detection limits available.
6 USP Purified Water & Water for Injection Process
Chlorine analyzer for de-chlorination
Ozone analyzer to monitor ozonation
& de-ozonation
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Monitoring Methods
Amperometric • Electrochemical process measures the change in
current resulting from chemical reactions taking place. A function of the analyte concentration.
• Probe based or three electrode sensors
• Three electrodes systems contain an anode split
into a reference and counter electrode providing a stable reading
• Flow through design, operating conditions, and
instrument sensor compensations(pH, temp, etc) are critical for accurate analysis
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Monitoring Methods
Colorimetric • Process measures the color intensity of a sample with
the addition of specific reagents. The intensity of color change is a function of the analyte concentration.
• Consists of a colorimeter(photometer) with a light source in the proper wavelength of the species to be monitored
• Injection of reagents, light source of photometer, and
flow through design are critical to proper operation and accurate analysis
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Chlorine • Reverse osmosis(RO) membranes are damaged by
chlorine. • Chlorine must be removed by
‒ Neutralization or destruction Sodium Bisulfite
‒ UV 254nm prior to introduction to the RO system. • To ensure membranes are protected it is desirable to
monitor the free chlorine residual present entering the membranes.
• Historically oxidation reduction potential (ORP) has been used to control the dechlorination process
• However since other species and factors influence the ORP industry is opting to monitor free chlorine residual rather than ORP.
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Deionization
• Once the water is partially deionized via the reverse osmosis system, final deionization to meet USP standard of < 1.3 µS/cm is accomplished by one of a three options:
‒ Second pass reverse osmosis ‒ Mixed bed ion exchanger ‒ Continuous deionization
• After deionization is complete the water is filtered
through a 2 micron filter: ‒ Then passes through an ultra-filter then to storage
for Pure Water processes or ‒ Through the distillation process and to storage for
Water For Injection processes.
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Chlorine Measurement • Free chlorine residual can be measured via colorimetric or
amperometric methods. • The colorimetric method employs N, N-diethyl-p-
phenylenediamine (DPD) reagent and pH buffer to measure the concentration of free chlorine.
• Monochloramine along with free and total chlorine can
also be monitored with DPD as follows. ‒ Zero measurement: Measurement of sample
background to compensate for light absorption effects (turbidity, sample color) not related to red DPD color
‒ Free residual chlorine (FRC) measurement Sample + Buffer + DPD dosing, immediate reaction
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Chlorine Measurement Continued
‒ Total Residual Chlorine 1 measurement; sum of free chlorine and monochloramine Sample + Buffer + DPD + KI dosing, immediate reaction -> Calculation of monochloramine content
‒ Total Residual chlorine 2 measurement: sum of all chlorine Sample + Buffer + DPD + KI plus 2 minutes to complete reaction Calculations: Combined Chlorine content
• If only free chlorine is to be measured a reagentless
amperometric chlorine analyzer can be employed.
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Amperometric vs. Colorimetric Chlorine Analyzer
Feature Amperometric DPD Colorimetric
Measurement Frequency Continuous 1 – 12 minutes
Minimum Conductivity Limit
≥ 5 µS/cm No limit
Accuracy ± 0.01 ppm ± 0.01 ppm
Reliable Yes Yes
Reagents Required No Yes
Chlorine feed/dechlorination control
Yes Yes
Data Validation Yes Yes
Monitor/sensor performance monitoring
Yes Yes
Reagent Level Monitoring N/A Yes
pH Measurement Optional Optional
ORP Measurement Optional Optional
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USP Water For Injection (WFI) • Water for injection requires high level of purity to ensure
the health of the patient. • Bacteria count must be < 10 CFU/ml which is 5 log or 105
removal of bacteria. • Sanitization which employs various chemicals only
reduces the bio-burden by 99.9% or 3 log (103). • The next level is disinfection is accomplished using
various chemicals or UV light. Disinfection removes up to 99.999% of the bio-burden or 5 log (105) leaving 10 microorganisms.
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USP Water For Injection (WFI) Cont. • The most effective means of reducing the bio-burden is
Sterilization accomplished by hydrogen peroxide, high heat, UV, ozone, radiation, and various chemicals.
• Sterilization removes 99.9999% or 6 log (106) of the bio-burden.
• Efficacy of these processes are ensured by the accurate
and reliable measurement at specific points in the water production process
• Control of disinfection processes such as ozonation and
de-ozonation can be achieved by employing analytical process technology with approved methods
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Ozone
• Ozone is an unstable allotrope of oxygen which reacts rapidly with most hydrocarbons to destroy biofilms, microbes, and organic residue.
• The strongest commercially available oxidant: 3000 times
stronger than chlorine. • Ozone when applied at appropriate concentrations will kill
or destroy the following: − Microorganisms − Viruses − Oocysts − Pyrogens − Reduces total organic carbon.
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Ozone • Ozone is made as follows:
3 O2 +UV 185 nm Energy → 2O3
• Other means of disinfection can be used such as heat,
however it requires substantial energy which is expensive.
• Ozone is easily generated, added, and removed.
• Ozone is destroyed via the below reaction:
2O3 + UV 254 nm Energy → 3O2
18
Ozone Measurement
• To ensure proper disinfection it is essential to monitor the ozone concentration.
• USP states Water For Injection (WFI) will contain "no
added substance”, therefore it must be shown that ozone is removed
• Selection of an accurate, reliable, low detection limit
analyzer to monitor and control your ozonation /de-ozonation process is important
• Ozone can be measured via the DPD colorimetric or
amperometric measurement method.
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DPD & Amperometric Analyzers
Feature Amperometric DPD Colorimetric Measurement Frequency Continuous 1 – 12 minutes Minimum Conductivity
Limit ≥ 5 µS/cm* No limit
Accuracy ± 0.005 ppm ± 0.005 ppm Reliable Yes Yes
Reagents Required No Yes Chlorine feed/dechlorination control
Yes Yes
Data Validation Yes Yes Monitor/sensor
performance monitoring Yes Yes
Reagent Level Monitoring N/A Yes pH Measurement Optional Optional
ORP Measurement Optional Optional
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Summary • Providing pathogen free Purified Water (PW) and Water
For Injection (WFI) is essential and closely regulated by the USP and FDA.
• Monitoring chlorine residuals and removal in the
deionization process is critical to protect the integrity of the reverse osmosis membranes and ion exchange resins in order to maintain performance and reduce costs and down time.
• Monitoring the ozone concentration and the removal of
ozone in WFI is critical to maintain public health and to meet USP and FDA standards.
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Summary Continued
• Proper application of continuous monitoring technologies available can:
− Avoid damaging ion exchange membranes and resins
− Reduce operating cost − Avoid costly down time − Ensure disinfection of the WFI loop − Ensure removal of ozone prior to production of final
WFI product − Ensure compliance with USP and FDA regulations − Avoid loss of product or fines
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Questions
Thank You for Your Attention
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