The United States Pharmacopoeia (USP) and European Pharmacopoeia (EP) regulations require total organic carbon (TOC) to be monitored in pharmaceutical waters. Implementing these guidelines is required for companies that bring drugs to the US market. These guidelines are contained in the USP monograph (article).
Among other functions, the USP states qualifications for sterility and packaging methods that delineate between the various specific types of water. However, there are two basic types of water preparation, Water for Injection and Purified Water. The analytical standards for these two types of water are very similar, differing in the fact that Water for Injection has stricter bacterial count standards and must also pass the bacterial endotoxin test. Preparation methods are very similar to a point, however, Water for Injection preparation must incorporate distillation or double pass reverse osmosis. Discussion of the various methodologies used in preparation of USP water applies equally to Purified Water (PW) and Water for Injection (WFI).
There are two main types of water purifies water (PW) and water for injection (WFI). Purified Water is water obtained by distillation, ion-exchange treatment, reverse osmosis, or other suitable process. It is pre-pared from water complying with the regulations of the U.S. Environmental Protection Agency (EPA) with respect to drinking water. It contains no added substances. And, Water for Injection (WFI) is water purified by distillation or re-verse.
These waters are used as ingredients in either dose form or bulk pharmaceuticals, so purity is critical. WFI is the purest grade of bulk water monographed by the USP, and is found in the manufacture of parenteral (injected), ophthalmic (eye drops), and inhalation products. The Fundamental objectives of the USP are:
- To maintain or improve the existing water quality
- Improvement of the reliability of the measured values by means of modern analytic instruments
- Reduction of the number of samples
- Authorization of the in-line measuring method
USP 23, and 24
I Before 1996, the quality of these waters was determined by a number of off-line, "antiquated" laboratory tests. The USP monograph 23 (and currently 24) replaced these tests with an on-line conductivity measurement as the initial marker. While PW only needs to meet a TOC limit, the WFI has to meet bacterial tests in addition to the TOC and conductivity limits. In this application note we will concentrate on the USP requirements for conductivity only. This change to an on-line conductivity measurement was precipitated by many desires including improving the reliability of the testing by using modern instrumentation, providing immediate alarms and options for quality control, eliminating sample collection and handling errors, and reducing the cost of testing.
The conductivity requirements mandated by USP are tiered in three stages:
Use In-line or grab sample methods to measure the conductivity and water temperature. This conductivity reading must not be temperature compensated. Compare these readings to the Stage I graph shown, or the values in table I. If the conductivity is below the limit stated for that temperature, the water meets the requirements. If the conductivity is above the limit, proceed to Stage Two. Advantages to In-Line measurement are:
- Real-time information for conductivity and temperature
- Immediate limit value alarm
- Data output for recording and
- documentation of the water quality
- Simple and reasonably-pricedmeasurement
- Avoiding errors due to sampling, handling and transport
Stage Two: Take a grab sample and measure the conductivity after equalization with atmosphere and temperature normalization to 25ºC. The water conductivity is below 2.1 μS then Stage Three is needed.
Stage Three: If Stage Two is exceeded, measure the pH of the grab sample and check conductivity against the results in table I of conductivity vs. pH. If the sample is within the limits, it passes. If it does not, the water is deemed unacceptable for PW or WFI use.
Yokogawa's conductivity transmitters and converters possess USP functions that make this seemingly complex and troublesome requirement pain free, and automatic. The SC202 two-wire conductivity transmitter has the USP23/24 Stage One table pre-programmed in its software. When enabled, the transmitter will send a FAIL signal when the water exceeds the USP limit. It also can display and transmit the uncompensated conductivity that USP mandates for compliance recording.
The SC450, DC402 and SC100 four-wire conductivity converters have additional USP features. These units have the ability to display and transmit the uncompensated conductivity for USP compliance, as well as the NzCl temperature compensated measurement, valuable for process control. The USP23/24 Stage One table is preprogrammed into these instruments, and a FAIL alarm will be given is the conductivity limits are exceeded. Alarms on these units can be dedicated as USP "warning" alarms with user defined safety margins. These "warning" alarms will inform the operator that his/ or her water is trending towards the USP limit, and will allow him/or her to take preemptive corrective action.
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