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The New USP <1231>
Water for Pharmaceutical Purposes

a detailed Overview

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GMP LOGFILE Features

2017-01-11

LOGFILE No. 01/2017 - Alert and action levels and specifications

Alert and action levels and specifications

An excerpt from the USP <1231> Download

by Fritz Röder

 

Introduction

This section is now much more comprehensive. It provides detailed explanations on the purpose of and the procedure for specifying alert and action levels and gives abundant examples.
A key factor in monitoring quality-relevant parameters is the speed at which determination methods deliver results. Process parameters are measured on site and in-line, with real-time values as results. When chemical attributes are measured, it usually takes several minutes for the values to become available. Monitoring microbiological parameters requires several days. To enable early detection of problems it makes sense to specify alert and action levels especially for quality parameters such as these, which are difficult to determine.

Examples of critical parameters measurements

Examples are given for process and quality-relevant parameters. In the process control a distinction is made between treatment and storage/distribution. Essential parameters in addition to water content (quality-relevant) always include temperature sensors for sanitising, or monitoring the concentration of the disinfectant. If the distribution system is sanitised with ozone, the corresponding measurement is also a part of quality-relevant parameters. In that case the calibration is obligatory.

Purpose of the measurements

As already mentioned, these provisions serve for the quality control of the product water as well as for process control and system monitoring. Specification of alert and action levels defines the moment as of which the operator should monitor a specific parameter more closely (alert level) or implement corrective actions (action level). Nevertheless, the parameters are still inside the specification even if the action level is exceeded (unless the action level and the specification have the same value). The validity of the collected data is important here. Furthermore, it is pointed out that alert and action levels do not have to be determined exclusively for microbiological considerations. Other parameters can also be subjected to early detection by defining limits.

Defining alert and action levels and specifications

The prerequisite for using these levels is the corresponding trending of the existing actual values. Historical data, if available, serves as a basis for determining the levels. If no historical data is available, fractions of the specified value can be applied for an initial definition (For example: 50% of specification = action level). However, the values thus obtained should then once again be critically scrutinized as soon as enough data is available. A distinction is made between a two-tier and three-tier approach. A three-tier approach includes alert level, action level and specification and offers the highest degree of certainty that no water will be used for production that does not meet specifications. The two-tier approach includes two limits, although there is no indication of what limits should be defined. However, if the specification for the parameter has been defined in the pharmacopoeia, it must also be included. A single-tier approach is not recommended as it offers no possibility for reaction. An approach of this kind could only be used for process control, provided that the attribute allows for it (e.g., residual hardness > 0° dH).

Alert level

The user defines alert levels so as to ensure that any excursion of the parameter can be detected early. Different methods exist to enable determination of a reasonable value. Possibilities include a double or triple standard deviation from the average value or a deviation in percent. It is also possible for an alert level to be exceeded due to a specific event (such as identification of unknown species). Exceeding an alert level does not necessarily call for action, but it could signal the need to increase the test frequency.

Action level

Action levels are based on the same historical data as alert levels, but they deviate more from the standard and thus lie between alert level and specification (provided that the three-tier approach is used). If the alert level is exceeded repeatedly, this is considered equivalent to exceeding the action level. In this case the Quality Assurance division is to be informed and a deviation investigation must be initiated. Additional measures can be derived from this.

Special alert and action level situations

In individual cases the levels can be handled differently from standard procedure. One example is a new water system with product water stored at ambient temperature. Initially no historical data is available. In addition, microbiological as well as chemical parameters change as a result of the ageing of the components. Operating parameters and sanitising frequencies are changed multiple times in a new system. Therefore, it may be helpful to adjust the levels more frequently. Another example given in this section refers to WFI systems. These systems reliably supply water of high microbiological quality. In other words there are usually no bacteria in the sample. Trending such data is not very successful. In such cases, >0 CFU/ml could also be specified as the alert level. The action level could be a multiple of the >0 CFU/ml finding.

Specifications

They are usually given in the relevant pharmacopoeias. As discussed above, this does not apply to microbiology, in which only action levels can be found. However, it is clearly expected of manufacturers that they define their own specifications based on risk. These values should not exceed the action levels given in the pharmacopoeias. Exceeding the specified limit is to be considered an out-of-specification (OOS) result, which will lead to a corresponding investigation including root cause analysis as well as suitable remedial actions (CAPAs) and the assessment of further use of the manufactured drugs.

Source water control

The last section of USP <1231> was not significantly altered within the framework of the revision. The source water should be tested at regular intervals and comply with drinking water regulations. If limits are exceeded the first step is to contact the provider. In addition, disinfection or filtration may remedy the situation.

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The pdf download USP <1231>: Water for Pharmaceutical Purposes highlights the following aspects of the new USP <1231>:

  • Short Overview – What is USP<1231> and what is new?
  • Detailed overview with explanations and important notes
  • Source water considerations
  • Monographs of water qualities
  • Validation and qualification of water systems
  • Design and operation of water systems
  • Sampling
  • Chemical Evaluations
  • Microbial evaluations
  • Alert and action levels and specifications#

Author:

Fritz Röder
Allergan plc

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