The aim of the paper is to sketch some tentative elements of a political economy of the production, control and interpretation of technical norms in the pharmaceutical industry. It seeks to follow the life of norms, from their negotiation and production to their implementation at the level of the firm. It builds on the historical strands of institutionalism to analyse the social and institutional construction of an industry, which is deeply structured by regulations and standards. The first part sketches an institutionalist view of norms as institutions and as crucial instruments in the art of governing, and on the determinants of their evolution.
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Download the magazine. Instrument manufacturers have worked to develop efficient online analyzers to perform continuous monitoring of certain parameters. These instruments have been known for a number of years but are not always used.
Hence Annex 15 of Good Manufacturing Processes and the PAT Process Analytical Technology working party tend to favor the continuous analysis of key parameters, since these enable round-the-clock monitoring and lead to greater responsiveness in the event of drift.
These measures make it possible to continuously validate the quality of water for pharmaceutical use in distribution systems or loops. We will examine the key parameters in WPU distribution loops and conclude with aspects related to the water intended for human consumption potable or drinking water entering the plant.
The pharmaceutical industry must know and control the quality of this drinking water since it is a key factor determining the quality of the water for pharmaceutical use and the treatments to be applied. Key parameters. TOC can be defined as a source of nutrients for the bacteria that could develop in WPU loops biofilm.
Sometimes the contaminants come from the decomposition of materials contained inside WPU distribution loops. The major risk is the development of a biofilm inside cold WPU distribution loops, particularly due to back contamination. Certain cold points of use of hot WPU water distribution loops can also be contaminated. Ozone This is a powerful oxidant used to sanitize cold bulk purified water distribution loops, primarily to prevent contamination and, in extreme cases, to destroy a biofilm.
Measurement principles. Hence the conductivity related to the temperature indicates the total mineralization status of water. Since the curve is not linear, it is not sufficient to introduce a correction coefficient. An alternating voltage is applied to the electrodes in contact with the solution to be tested. The conductance is used to calculate the conductivity, concentration or specific resistivity of the solution. This is a very effective method for measuring low conductivities.
The measurement resolution must be at least 0. And the measurement is always performed without any compensation related to temperature, with pharmacists preferring to use raw values. Chapter of the USP defines a three-stage test not described in this article to make sure that the conductivity of the water clearly complies with the quality limits. In practice, the indirect method is very easy to implement because a cell can be certified without dismantling the sensor in place, and it can be used to control the whole system at the same time transmitter, sensor and cable.
It is also possible to verify the transmitter and cable only, using certified test resistors. In practice, when verifications are erroneous, the only option available to pharmacists is to adjust the cell constant. Logically, the sensor that is drifting should be replaced or cleaned, because the only explanation for this drift can be clogging or, in the worst case scenario, an intrinsic modification in its geometry due to deterioration of the electrode itself.
The online measurement points are the inlets and outlets of the WPU production system and, obviously, loop starts and returns. Today, the following main methods can be found on the market for determining TOC :. Oxidation In thermal oxidation processes, the organic compounds are broken down at high temperature. Hence undissolved components solid matter or materials from abrasion can also be completely broken down into CO 2. In applications with high organic loads for example municipal wastewater , this is a tried and tested method.
In coupled oxidation processes, the components are broken down by a powerful oxidant, such as persulfate, as well as UV radiation. However, it requires chemical products of high purity and a purge gas, which are not insignificant factors in terms of cost. This implies a lower measurement range and a low-conductivity sample. However, for applications in pure and ultra-pure water, this method is reliable and less expensive.
Detection NDIR detection : This method employs an infrared detector that measures the CO 2 generated by determining the amount of infrared light absorbed by CO 2 at a known distance. Detection by conductivity sensor : the CO 2 generated has an impact on conductivity, increasing its value.
The calculation is made using known conversion tables. In the pharmaceutical industry, the regulations are stipulated by pharmacopoeias:. Since TOC is a nutrient for bacteria, it goes without saying that water for pharmaceutical use included in the composition of medicinal products must be free of TOC in order to prevent bacterial proliferation and the development of a biofilm.
In this process, the online analyzer sucks in the sample from the loop. After the first conductivity measurement, the sample enters a UV reactor. Inside, the organic carbon present in the water for pharmaceutical use is oxidized into CO 2. This CO 2 in turn increases the conductivity measured. This conductivity is measured by a second sensor positioned after the UV reactor. The difference between the second and the first conductivity measurement can be used to calculate the TOC on the basis of the following principle:.
This recognized method is the simplest and the quickest. The response time is less than 2 minutes. Monitoring of the process is continuous, making it possible to control the WPU distribution loop. This type of equipment is an economical choice because the investment, operating and maintenance costs are very reasonable. This measurement principle is very well suited to water for pharmaceutical use.
The TIC is not very high and is essentially composed of CO 2 , leading to reliable results over the range 0 to ppb. This article does not describe all the methods, but for the manufacture of certified measurement calibration and validation solutions:. This test verifies that the analyzer is capable of oxidizing both single and complex bonds:. The success of the test is expressed in relative efficacy:. We thereby ensure the suitability of the analyzer and it is consequently validated.
In practice, this test is performed every 6 months, with maintenance also performed at the same frequency. The characteristic points to be monitored are:. Control of additives to ensure a continuously effective concentration and subsequent monitoring to ensure their removal should be designed into the system and included in the monitoring program. The measurement principles used are the electrochemical method and the spectrophotometric method. The sensitivity of the amperometric electrochemical sensor is good.
If no current is induced, there is no ozone. The major drawback of this technology is related to polarization and depolarization phenomena. The steady presence of ozone is required to polarize the sensor. Electrochemical measurement amperometric sensor presents a major reliability disadvantage concerning measurement of ozone absence. The fact that low ozone values are measured with this type of sensor has a significant impact on response times, which are prolonged.
An additional disadvantage is that of maintenance replacement of the membrane , making it necessary to interrupt measurement and perform a calibration and polarization procedure, which takes time sometimes as much as 4 days. The ozonizer is then switched to forced-mode operation to reach a value of at least ppb, controlled using a reference method. The reference method is spectrophotometry. In the presence of ozone, the addition of these reagents to the sample causes a color to develop, measured by the spectrophotometer.
The intensity of this color is directly proportional to the ozone concentration. The disadvantage of this method is that it uses specific reagents, but guarantees a much more reliable ozone measurement and, above all, guarantees the measurement of absence since there is no depolarization. A low range point and the zero are determined before each measurement. There is no time wasted following maintenance on this instrument since there are no polarization phenomena. The measurement is reliable from the very first measurement.
However, it is necessary to specify an essential point for the measurement of ozone: Water sampling. There are no regulations concerning ozone testing but recommendations exist:.
Continuous measurements of these different parameters are qualitative and economic advantages. These measurements make it possible to continuously guarantee the quality of water for pharmaceutical use and enable greater responsiveness.
Given the cost associated with nonconformities and the time needed to manage them, there is no doubt that these online testing systems are now essential for the management of installations.
We can already consider that drinking water is a water for pharmaceutical use since it supplies the whole site. The site must have regular tests performed by approved laboratories and must monitor a few parameters:.
Trained in the water trades and related components such as electrical engineering and civil engineering infrastructure, he began his activity in industry, for more than 5 years, at Suez and OTV, in various operating services and work supervision. He was faced with a number of issues related to water quality and the importance of analytical tools. In this context, he actively participates in the development of the pharmaceutical market. Linkedin Send by email. Pharmacopeial Convention Inc.
Area membri. Area membri Logout. Cleaning and disinfection program part of the lifecycle approach: a risk based rather arbitrarily imposed approach. Continuous measurement in water for pharmaceutical use WPU. Measurement principles 2. The difference between the second and the first conductivity measurement can be used to calculate the TOC on the basis of the following principle: This recognized method is the simplest and the quickest.
This article does not describe all the methods, but for the manufacture of certified measurement calibration and validation solutions: the equipment must be calibrated: using a standard solution the limit of detection must be less than 50 ppb the determination of TOC must be performed by subtracting TIC from TC a crucial parameter: the SST System Suitability Test must be performed every 6 months.
Performance of the SST to ensure that the previous 6 months are validated. Performance of maintenance, replacement of recommended components, such as the UV lamp, for example.
Performance of full-scale calibration on the whole analyzer optional but recommended. Performance of the SST for validation and start of the next 6-month period. The characteristic points to be monitored are: the WPU distribution loop return the performance of measurements at distiller exits may be recommended but especially at ion exchange resin exits.
Brevitas provided GMP advice and coaching which facilitated the successful execution of the OSE, with no observations. In order to meet the constant demand for their products, our Global Pharmaceutical client retained the services of Brevitas consultants to provide compliance support and address open Quality Notifications by special investigation and effective root cause corrective actions. Our client required an approach to categorize critical utility system components, to allow for the adjustment of maintenance frequencies and verify the accuracy of information within SAP. Brevitas developed a standardized assessment method and successfully applied it to 30 critical utility systems across the site.
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