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Selecting an Effective Pipette Calibration Frequency
By George Rodrigues, Ph.D., Senior Scientific Manager, ARTEL
In the June 2006 issue of Pharmaceutical Processing, we discussed the most
common methods for calibrating and verifying liquid delivery instrumentation.
These methods are gravimetry, fluorometry, photometry and Ratiometric Photometry™,
and each can be a useful tool in the continual battle against false data and non-compliance.
As a laboratory manager or responsible scientist, you need to decide not only
which tool to implement, but also how often to pick it up and use it. Even the
best tool accomplishes nothing if it’s never put to use.
In previous articles in the Perspectives on Instrumentation series, we’ve established
the ubiquity of liquid delivery instruments in pharmaceutical laboratories, with
tens of thousands of automated pipetting and dispensing workstations and about
15 million pipettes in active service worldwide. We’ve also discussed the prevalence
of instrumentation error, with research indicating that in some laboratories,
30 percent of pipettes are malfunctioning at any given moment.
Since pipettes and other liquid delivery devices produce crucial laboratory data, the implications of malfunction are grave. One of the most critical aspects to ensuring pipette accuracy and precision is calibration frequency. This article will help you diagnose your pipette population and determine a schedule that meets your laboratory’s requirements and keeps your lab tuned up and running smoothly.
How Pipettes Fail
The mechanical action pipettes used in today’s laboratories, unlike the original glass pipette, contain many internal parts, and not all pipette failures are evident. Sometimes the operator can discern that the pipette is not operating correctly, either visually or by the feel of the pipette action. However, when the internal mechanism of a pipette fails and it is not obvious to the operator, a silent failure has occurred. For example, a corroded piston or leaking seal might cause a pipette to deliver incorrectly - sometimes by a wide margin – and these errors usually go undetected by the operator.
Not only are most pipette failures silent, but they are also often random. Failure is considered random when caused by accidents, misuse or other unpredictable events. For example, an operator may accidentally draw liquid into the body of the pipette, causing piston corrosion or premature seal wear. Random failures cannot be prevented by infrequently scheduled maintenance.
Random or unpredictable failures typically represent at least 90 percent of all pipette failures. In contrast, predictable (hence preventable) failures are those that arise from normal wear and are dependent on factors such as frequency of use and time since last maintenance. Predictable failures represent 10 percent or less of all pipette failures. An effective calibration program can help laboratories minimize the risk of pipette failures and reduce liquid delivery error.
Determining Calibration Frequency
To determine a suitable calibration frequency for a laboratory’s pipette population, several factors must be evaluated including Mean Time Before Failure, target reliability levels, quality control principles and regulations.
Mean Time Before Failure
The average rate at which failures occur can be expressed as Mean Time Before Failure (MTBF). To determine MTBF, a group of pipettes is tracked to determine how long it takes each pipette to fail. A failure is defined as performance that falls outside the laboratory’s established tolerances. The mean of all the failure times is the MTBF for that specific group of pipettes, and is often in the range of 2 to 4 years, but can be shorter or longer depending on laboratory conditions.
Target Reliability Level
Another essential element in the determination of calibration frequency involves establishing a level of target reliability for liquid delivery, which is based on the quality mandate of a given laboratory. Reliability level is expressed as a percentage: 95 percent reliability means that, at any given moment, 95 percent of pipettes in a population are working correctly, while 5 percent are generating incorrect results.
Factors to consider when establishing a target reliability level include assay precision, the potential impacts of failed pipettes on critical laboratory processes, legal defensibility of results and production batch release decisions. Compliance with regulatory guidelines is also important. Many pharmaceutical organizations set a reliability target of at least 95 percent.
Given the established target reliability level for a laboratory and the MTBF for the pipette population, the graph in Figure 1 can be used to determine the required calibration frequency.
(Insert Figure 1 here. Title: Calibration Frequency for Pipettes, Based on Target Reliability Level and Estimated MTBF)
Suppose that the required target reliability level is 95 percent and the MTBF is two years. To determine the appropriate calibration frequency, follow the line indicating MTBF of two years on Figure 1 until it meets the 95 percent level on the Y-axis. The corresponding point on the X-axis indicates the required calibration interval, which, in this case, is approximately three months. Therefore, checking the pipettes at three-month intervals will provide assurance that pipette performance meets the established quality mandate.
QC Principles
Mechanical action pipettes are precision laboratory instruments. Therefore, they should be subject to the same quality control principles as other sensitive instruments, such as spectrophotometers and balances.
The more frequently calibration is performed, the sooner malfunctioning pipettes
will be detected and taken out of service. For this reason, more frequent calibration
can greatly reduce the amount of laboratory data that might be impacted by a failed
pipette. Basically, the longer a defective pipette remains in service, the more
likely it is to have failed and the greater the chance of potentially impacted
data. It’s a double whammy.
Regulations
In order to build quality into pharmaceutical processing laboratories, the instruments
used must be in good condition and properly calibrated. Regulations and standards
published by organizations such as the International Organization for Standardization
(ISO) and the U.S. Food and Drug Administration (FDA) provide minimum requirements
that help ensure the quality of laboratory results. These form the groundwork
upon which a laboratory should establish the frequency of pipette calibration
as part of good quality control practices.
Regulations specify that all laboratory instruments used in production, including pipettes, be regularly calibrated at an appropriate frequency. This frequency should be related to the amount and criticality of pipette use and the laboratory’s MTBF experience.
Conclusion
Whenever pipettes are used in pharmaceutical laboratory operations, the corresponding
laboratory results depend on accurate and precise liquid delivery. Since pipettes
are subject to silent and random failures and have a high rate of failure as compared
to other laboratory equipment, the most important aspect of pipette quality control
is maintaining a calibration frequency that achieves sufficiently high reliability.
Calibration frequency is a function of the MTBF of the pipettes, the laboratory’s
desired reliability level and its established QC principles. Also keep in mind
the important regulatory guidelines pertaining to your laboratory, and use these
as a foundation for establishing an appropriate calibration frequency.
For the next article in the Liquid Delivery Instrumentation Insight column, we will focus on a liquid delivery issue of your choice. Send your question to grodrigues@artel-usa.com and look for the answer in the November 2006 issue.
About the Author: George Rodrigues, Ph.D., is Senior Scientific Manager at
ARTEL, a leading innovator in liquid delivery quality assurance. Rodrigues is
responsible for developing and delivering communications and consulting programs
designed to maximize laboratory quality and productivity through science-based
management of liquid delivery. Rodrigues earned his BS in Chemical Engineering
at the U.C. Berkeley, and a Ph.D. in Chemical Engineering at the University of
Wisconsin. Dr. Rodrigues can be contacted at (207) 854-0860 or grodrigues@artel-usa.com.
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