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

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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

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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