On the importance of monitoring the parameters of the treated water supply used in the manufacture of water for pharmaceutical use on production premises.

With regard to the physicochemical parameters of water for pharmaceutical use, we very frequently discuss the analytical monitoring of purified water (PW) loops and of water for injectable preparations (WFI), with inline measurements of conductivity, dissolved ozone and TOC, but we talk less frequently about the quality of the raw water used for this production. However, the water which enters the factory must already be considered water for pharmaceutical use.

First of all, the quality of the water used in production must comply with drinking water criteria, therefore, be delivered either by the competent public or delegated services, or, as is often the case, be produced by drawing it from the natural surface environment (river…) or aquifer (drilling), insofar as the quality of this raw water complies with prerequisites for human consumption (see DECREE OF 11 JANUARY 2007). This article does not discuss raw water treatment systems, but the main physicochemical parameters of treated water that enters the producer’s premises.

 

1. Reminder of the regulatory context of water for human consumption
The French Ministry for Health, in accordance with the European directives, sets the standards applicable in France, for the control of probable water quality.
They are set out in the Decree of 11 January 2007 on the limits and the quality benchmarks for raw water and water for human consumption.

It should be understood that not all raw water can be used to produce drinking water. It must comply with criteria and is evaluated by 39 bacteriological and physicochemical parameters (including pesticides and heavy metals). So raw water must be treated. The objective of treatment (although this is not the subject of this article) is then to protect consumers from pathogenic microorganisms and impurities that are unpleasant or which endanger health. Surface water will always require complete physical and chemical treatment while groundwater may only undergo disinfectant chemical treatment, so long as it is not contaminated by iron, manganese, arsenic, nitrates and phytosanitary products.

To end on the regulatory aspect, these decrees set, both for raw and treated water, microbiological, physicochemical, organoleptic (taste and smell) quality limit values and parameters indicative of radioactivity. According to the EMA and the FDA, once the treatment has been carried out, the quality of the water used to produce water for pharmaceutical use must meet the criteria for drinking water.

 

2. Analytical monitoring guarantor of pretreatment
Today, the key physicochemical parameters can be easily monitored on a continuous basis, which will guarantee that the quality of the incoming water does not deteriorate, and indeed, does not cause problems with the efficiency of the producer of water for pharmaceutical use (ultrafiltration, mixed bed resin, multi-stage reverse osmosis device, EDI, thermocompressor etc.…).

The simplest recommended parameters to monitor are the following although this list is not exhaustive:

  1. Ammonium (NH4)
  2. Total Organic Carbon (TOC)(1)
  3. pH and temperature
  4. Free chlorine and/or total chlorine
  5. Conductivity
  6. Turbidity
  7. Silica (SiO2)

 

2.1 Ammonium(NH4)

Although ammonium is of natural origin, the water must not however contain more than 0.1 mg/l of this substance. Ammonium is quite simply a source of nitrogen (of nutrients) for bacteria. In addition, in the nitratation phenomenon (transformation of ammonium into nitrates), other bacteria that practice anoxic respiration use nitrates as a source of oxygen, called bound oxygen, to respire. This results in the formation of nitrites which have known harmful effects on health. Ammonium can be monitored and controlled with simple analyzers, by a selective probe for example.

The principle is simple: the sample passes into an analysis chamber in which are immersed a probe with a selective membrane and the reference electrode. The ammonium ions passing into the measurement probe across the membrane will vary its potential relative to the reference electrode in proportion to their concentration (Nernst law). The software transforms the signal and displays it in millivolts on the transmitter directly in mg/l of NH4.

 

2.2 Organic Carbon
TOC is very widely used and very well known for monitoring organic contamination in loops of water for pharmaceutical use, and is a very important element to monitor in “raw” water to avoid the provision of upstream sources of carbon, and the contamination of the producer. Although there are very successful complex analyzers for measuring TOC by thermal and chemical oxidation, there are also very simple methods for the ongoing detection of a source of organic pollution in this quality of water, using optical measurement: measurement of UV absorption at 254 nm or SAC 254. We speak of absorbance units or, or conversely of % transmittance; or UV absorption/distance unit (UVA: m-1, cm-1). This is the absorption of the sample at a wavelength of 254 nm over a known measuring cell distance.

At this wavelength, the light absorbed by the sample is directly proportional to the dissolved organic molecules. On water matrices with a stable composition, it is even possible to make precise correlations with TOC, DCO, based on recalibration of the apparatus after several comparative measurements in the laboratory, by entering the slope-intercept characteristics in the software (slope and offset in the common language of instrumentists).

-1 or cm-1the lower the aqueous load of dissolved organic materials and vice versa. Conversely, this technique cannot be used on water with very high loads and will not be sufficiently accurate for purified water.

The quality benchmark value for this parameter is 2 mg/l or ppm (parts per million) of TOC. This concentration should not exceed 10 ppm in raw water drawn from the natural environment.

 

2.3 PH and temperature
pH remains a criterion of quality, as the water must not be too acid or too basic, that is neither corrosive nor encrusting. pH is always measured with temperature, as it varies with this parameter. So that everyone speaks the same language, the value is very often converted to that at 25°C (referred to as compensation).
On pH analyzers, there is therefore always a temperature probe, either separate, or combined. The principle of pH measurement is based on the same principle as measurement of ammonium, except that here, the glass electrode is selective for H+ ions which vary its Redox potential relative to the reference probe. In accordance with the law pH = -log [H3O+],the software transforms and displays the pH, with a value of between zero and 14. A solution is called acid when the pH is below 7, basic when it is above 7 and neutral when the pH is equal to 7.

 

2.4 Free and total chlorine

Chlorine is the most commonly used disinfectant agent that is added to water. Indeed drinking water must be disinfected and disinfecting (it must always contain a residual amount of active chlorine residual). Chlorine, in its active form “hypochlorous acid” is a powerful disinfectant agent possessing remanent properties, that is, it will continue to act partially even after its addition has been stopped (not indefinitely, if its injection is stopped). Chlorine decomposes in water in a pH-dependent manner, and its disinfectant ”active chlorine” form predominates at precise pH values: between 4 and 7.5.

“Free” chlorine, is in fact the form of these three chemical species, gaseous, HClO and ClO.
In practice, for this quality of water there is a simple measurement method based on 3 electrode amperometry. A defined voltage of 1100 mV is applied to the terminals of a platinum anode and cathode, continuously corrected by a reference electrode, which confers greater stability on the sensor. The oxidizing agent is reduced on the sensor terminals, generates a transfer of electrons, and therefore a very low µA current, directly proportional to the value of the active chlorine. The value is converted to free chlorine in a pH-dependent manner.

 

 

Specific case of chlorine:
Active chlorine will combine with ammonia to form what is called combined chlorine (or chloramines). Mono, di and trichloramines are distinguished, which form in a chain reaction until they are released in the form of trichloramines if chlorine quantities are pushed to the “breakpoint”(2). In summary, all the chlorine added above this quantity remains in the form of residual free chlorine, in drinking water, the free chlorine residual must be 0.1 ppm at the point of delivery.

This combined chlorine is partly responsible for the taste and smell of water. It can be understood therefore why water must contain a low basic quantity of ammonium, to limit input of chlorine. Effectively, the free chlorine will be consumed and must always be present in sufficient quantity to provide disinfection, therefore it must be monitored, indeed regulated.

And it is therefore all these forms of chlorine (free and combined) which constitute total chlorine, and it is understandable that a reduction in free chlorine and an increase in total chlorine will cause ammonia pollution.
Total chlorine is measured by different methods, but the surest and most reliable method is the standardized reference DPD method (DIN EN ISO 7393-2 and APHA 4500-CI-G). The addition of the DPD, in buffered medium, in the presence of potassium iodide, after a two-minute reaction, reveals total chlorine in the form of a pink complex, whose intensity is directly proportional to its concentration. This intensity is read with a spectrophotometer at a wavelength of around 515 nm.

 

 

In practice, the analyzer shown above produces this measurement: liquid reagents are added to a chamber into which the sample is introduced, then stored for two minutes by means of a solenoid valve before being read by the photometer, followed by evacuation and rinsing, until the next cycle.
NB: the chlorine will be removed by chemical means(sodium bisulfite) or physical means (active carbon) as the resins or filtration membranes downstream very sensitive to chlorine and chloramines, and must not be damaged. Measurement of the absence of total chlorine upstream of these processes is essential.
Only the colorimetric method performs this role satisfactorily, as it is not subject to the depolarization phenomenon (unlike amperometric sensors).

 

2.5 Conductivity
This is a non-specific indicator of mineral pollution (ions) which is expressed by the capacity of the water to conduct an electric current. Measurement of conductivity is linked to Ohm’s law:U = R x I, U being the voltage in volts, R the resistance in ohms and I the current in amperes.

The conductivity C, expressed in Siemens per centimeter is the result of the following equation:
C = k x G, where G is the reciprocal of the resistance expressed in Siemens and k, constant expressed in cm-1.

This constant k is a value that is linked to the constitution of the measurement electrode: it is the ratio between the distance separating the electrodes and their surface area:

The conductivity of a solution depends on:

  • its ionic concentration,
  • the valency of the ions,
  • the nature of the solution (acid, basic or neutral),
  • and also temperature.

Thus, conductivity, in association with temperature conveys the total mineralization level of water.

 

In practice, for inline measurement, manufacturers have developed sensors most often composed of 2 or 4 electrodes in noble materials (316 stainless steel, titanium, platinum), according to the principle referred to previously. Voltage is applied to the electrodes in contact with the solution to be analyzed. The conductance allows the conductivity, concentration or specific resistance of the solution to be calculated.

The quality benchmark value for water coming into the factory: conductivity must be between 200 and 1100µS/cm at 25°C.

 

 

2.6 Turbidity

Turbidity defines the cloudy appearance of the water. The elements responsible are in fact, colloids derived from the humic decomposition of plants and animals, which are particles in the order of microns with an electronegative charge and which do not settle, because they constantly repel each other. Colloids are a substrate for bacterial growth, and it is because of this that the lower the turbidity level, the better the water quality for this parameter. The term limpid water is commonly used.

Turbidity is measured using optical technology, in accordance with a standard agreed on by all manufacturers, so that everyone presents a result on the basis of the same reference document. This is the ISO 7027 standard.

A light beam (white light [USA], LED infrared [Europe]) is transmitted through the sample containing the colloids, and diffraction, refraction and diffusion phenomena perform their function. It is because of this that only light transmitted at an angle of 90° to the photosensitive cell enables calculation of turbidity, finally expressed by the difference between the intensity of the emitted light and that perceived. The result is displayed in NTU for NEPHELOMETRIC TURBIDITY UNIT. There are conventional analyzers, where the beam first passes through a glass wall before the sample, which implies soiling, and the need for regular cleaning (wipers /retro-washing/ ultrasound) to avoid measurement deviations.

Today there are “contactless” devices, which guarantee measurement without deviations and without consumables, as the water is never in contact with the measurement optics, and nothing is positioned between them and the sample, excluding contact with air. Turbidity here is thought to be a good indicator of protection by osmotic membranes, although it does not replace the clogging index. The quality limit for our topic is 1 NTU, although the quality benchmark value is likely to be 0.5 NTU. (Realizing that 2 NTU is authorized for tap drinking water).

 

2.7 Silica
Although there is no clear standardization for silica, it is however here an extremely important parameter depending on the nature of the producer. Silica is present naturally in water, in different forms, ionized silica: SiO2-, colloidal silica, complex silicates (combination with iron, aluminum, magnesium, potassium…). All these forms are expressed as SiO2-.

As the solubility of silica diminishes with increases in pressure and temperature, it will be understood that it is essential to maintain the silica level as low as possible in the incoming water of certain producers and particularly distillers, who may find themselves vitrified by the silica with complete loss of their efficiency.

Silica levels are determined by spectrophotometric analysis, in the same way as chlorine, dissolved silica is measured here using molybdenum blue at a wavelength of 810 nm. The intensity of this coloration will be proportional to the concentration of dissolved silica.

 

This complex reaction takes place in several stages in the photometry chamber:

– Reaction of silica and orthophosphates with ammonium molybdate (1) in an acid medium (2) (yellow color).
– Destruction of phosphomolybdic acid by oxalic acid (3) (elimination of interference caused by phosphates).
– Reduction of molybdosilicic acid by ferrous ammonium sulfate (4) into a blue heterocomplex.
– The reaction is heated at 45°C to catalyze the reaction.

The target values should be located in the region of 20 ppb (20 µg/l).

 

2.8 Metrology applied to this type of sensor (see glossary for definitions)
Although this is not the subject of this article, we can however indicate that these analyzers must obviously be monitored to ensure they are functioning correctly and acceptably and that they produce reliable results.

Regarding sensor technologies, like ammonium ISE or pH probes they will require weekly checks in one or several standard reference solutions. From a metrological perspective, we speak of verification or calibration. If the deviation is greater than 10%, it is recommended to carry out an adjustment that is to modify the slope and offset parameters of the sensor, in order to allow the equipment to perform in the intended manner.

For conductivity sensors, which are more stable over time, a monthly check using a benchmark probe or a certified field device will be sufficient, with adjustment if needed.

Optical technologies are recognized for being stable and for not deviating, and the metrological criteria are a little different, as there is not always a stable standard reference solution (in the case of chlorine, or ozone for example).
It is however possible to check systems with standard reference solutions when they exist, or else, and in accordance with NIST spectrophotometer verification standards, we can use filters or crystal standards, associated with national standards, in order to check for deviations in optical systems.

Finally it is always possible to take measurements using comparable field devices, called secondary standards associated with national standards and therefore certified, to calibrate and adjust the measurement devices under test as needed.

 

 

In conclusion, this article was written so that production resource managers might become aware of the importance of water quality upstream of the producer. The addition of physicochemical robots at certain strategic points in the factory will allow further improvement in the monitoring and availability of production resources and enable greater reactivity in the event of deviations, well upstream of the water loop and the user.The consequences of contaminated raw water, passing through pipework containing biofilms through lack of chlorine, for example, can be easily imagined. It could be a source of producer contamination … Therefore we note the importance of checking that chlorine is present in water entering the factory, although this chlorine must be subsequently removed so that processes operate correctly: the consequences could be fairly dramatic for membrane or resin pretreatments that are very sensitive to oxidizing agents, or clogging. This is why it is very important to monitor the absence of total chlorine upstream of a reverse osmosis device, to check that the activated carbon or bisulfite injection is operating correctly. In addition, monitoring turbidity provides a picture of what may contribute to membrane clogging.

It is therefore clearly a case of gaining from traceability, of increasing reactivity in the event of deviations in the incoming water, to put in place corrective actions as soon as possible. This avoids:

  • costly expenditure on curative measures (resins, osmotic membranes, intervention time…),
  • associated costs in case of production shutdown,
  • justifications and the production of associated documents.

From the metrological perspective, it should not be forgotten that these analyzers must be monitored and calibrated as necessary.

The parameters cited are not exhaustive, but represent a very good basis for achieving good performance.

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Gracia

Benjamin GRACIA – SWAN

Project manager SWAN France, after a BTS and a professional license in the water business, Benjamin Gracia has held various positions at SWAN France, including that of leading large national accounts. His passion for instrumentation and his technical expertise allows him to collaborate on value-added projects of the company.

benjamin.gracia@swan-france.fr

Schneider

Guillaume SCHNEIDER – SWAN

Sales Director SWAN France, from a Physical Measurement IUT then from a Business School, Guillaume Schneider has been working at SWAN for 16 years now. His dual technical and commercial skills and his experience in pure and ultra pure water applications acquired in the semiconductor and energy industry allow him to have a critical eye on the monitoring of physico-chemical parameters online. Passionate about technology, he is in charge of the technical team at SWAN France.

guillaume.schneider@swan-france.fr

Glossary

EMA : European Medicines Agency
FDA : Food and Drug Agency

Bibliography

Last decree of January 11, 2007 relating to the limits and references of qualities of raw water and intended for human consumption.
Internal swan documents.

Definitions

Total Organic Carbon These are the forms of carbon present in water, they can be in dissolved form or not. This is a so-called organic pollution criterion. Carbon can come from the decomposition of animals and plants, and it is also a source of carbon for bacteria, which can therefore grow.

Break PointThis is the method used to remove chloramines from water (responsible for taste and odor). Chloramines are formed by the action of chlorine on ammonia, which is also present in organic matter, in the form of urea for example. For lambda drinking water, we perform the following laboratory test, to ensure that the chlorine dosage will be sufficient to maintain a residual chlorine free at the delivery point. This involves injecting chlorine into the water sample, and making regular measurements of free chlorine over time. Initially, the active chlorine is consumed to form in chain the mono, di and tri-chloramines (gaseous), finally, after a certain time, all the added chlorine is measured in free chlorine, because it does not there is more ammonia for the reaction. The inflection point of the curve is called “Break Point”.

ISO standard en 7393-2 – for the measurement of chlorine Water quality – Determination of free chlorine and total chlorine – Part 2: N, N-diethylphenylene-1,4 diamine colorimetric method for routine checks.
This document specifies a method for the determination of free chlorine and total chlorine in water, easily applicable in laboratory and field tests. It is based on the measurement of the absorption of the red DPD compound in a photometer or on the measurement of the intensity of the color by visual comparison of the color with a regularly calibrated standard scale. This method is suitable for drinking water and other waters, where additional halogens such as bromine and iodine, and other oxidizing agents are present in almost negligible amounts. Seawater and waters containing bromides and iodides constitute a group requiring the implementation of particular processes. This method is applicable in practice to concentrations, in terms of chlorine(Cl2) , for example between 0.000 4 mmol / l and 0.07 mmol / l (that is to say between 0.03 mg / l and 5 mg / l) for total chlorine. At higher concentration, the test sample is diluted. In general, the method is applied as a field method with mobile photometers and commercially available ready-to-use reagents (liquid reagents, powders and tablets). It is essential that these reagents meet the minimum requirements, and that they include the essential reagents and a buffer system for adjusting the pH of the measurement solution to a range generally between 6.2 and 6.5. In case of doubt regarding the pH values ​​and / or the unusual buffering powers that the water samples could present, the user must check and, if necessary, adjust the pH of the sample to the required range. The pH of the sample must be between 4 and 8. Adjust, if necessary, using sulfuric acid or a solution of sodium hydroxide before the test. A method allowing the differentiation of combined chlorine of monochloramine type, of combined chlorine of dichloramine type and of combined chlorine in the form of nitrogen trichloride is presented in Annex A. Annex C presents a procedure for the determination of free chlorine and total chlorine in drinking water and other types of slightly polluted water, with flat single-use tanks filled with reagent, used with a pump or a colorimeter with a mesofluidic channel.

Source: AFNOR APHA 4500-CI G: equivalent to American standards for chlorine (= ISO EN 7393-2)

TurbidityISO 7027-1: 2016 specifies two quantitative methods for determining the turbidity of water, using optical turbidimeters or nephelometers:
a) nephelometry, which is a method by measuring diffuse radiation, applicable to waters with low turbidity (for example, drinking water);
b) turbidimetry, which is a method by measuring radiation attenuation, more suitable for waters with high turbidity (for example, waste water or other turbid water).
The turbidities measured according to the first method are expressed in nephelometric turbidity units (NTU). They are generally between 0.05 NTU and 400 NTU. Depending on the characteristics of the equipment, this method can also be used for water with higher turbidity. There is a numerical equivalence between nephelometric turbidity units (NTU) and formazine nephelometric units (FNU). The turbidity measured according to the second method is expressed in formazine attenuation units (FAU), it is generally between 40 FAU and 4000 FAU.Source: International Organization for Standardization

ISE Ion Sensitive Electrode: measurement probe of a selective sensor to a given element, such as Ammonium probe, or pH measurement probe for example.

EtalonIt is a benchmark, with value and uncertainty, to which we compare ourselves to establish the accuracy and traceability of its results. The lower the standard’s uncertainty, the better its quality. We go from the working standard (high uncertainty) to the primary standard (very low uncertainty).
Source: LNE (National Laboratory for Testing, internet)

CalibrationIt is the comparison of the values ​​of a measuring instrument with those of a standard, by associating the uncertainties. This comparison estimates the bias (trueness) of the instrument. The values ​​obtained by a calibration are recorded in a “calibration certificate”. Calibration can be performed at several points in the measurement range of the equipment to be calibrated. This gives a calibration curve.
Source : LNE, internet

Adjustment or adjustment Set of operations performed on a measurement system so that it provides prescribed indications corresponding to given values ​​of the quantities to be measured. NOTE 1 Various types of adjustment of a measurement system are zero adjustment, offset adjustment, range adjustment (also called gain adjustment).
NOTE 2 Il convient de ne pas confondre l’ajustage d’un système de mesure avec son étalonnage, qui est un préalable à l’ajustage.
NOTE 3 After an adjustment of a measurement system, the system generally requires to be recalibrated.
Source: International vocabulary of metrology, internet

NIST The National Institute of Standards and Technology or NIST is an agency of the United States Department of Commerce.
Source : internet