Recently, Quality Risk Management (QRM) has become a mandatory regulatory requirement for drug manufacturers. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) publish guidelines and requirements which customers and vendors are expected to follow. Guidelines such as “Process Validation: General Principles and Practices” by the FDA and Annex 15 issued by the EMA offer input to help drug manufacturers design processes correctly.
Based on the new process validation model published by the FDA (Figure 1), validation is never finished, but is instead a process of continuous improvement. Maintenance and calibration activities of instruments are part of stage three in the model.
QRM is an overall and continuous process to minimize product quality risk. Instrument calibration/verification interval definitions are part of QRM risk analysis, and guidelines for these procedures are described by the FDA and EMA accordingly. Selecting the correct instrument for the application is absolutely crucial in the design phase of the project, and the criticality of the measuring point defines the required reliability and measuring accuracy of the instrument.
ISO 9001:2008 section 7.6 requires instruments to be calibrated or verified at regular intervals. The following basic requirements have to be fulfilled:
• Calibration/verification must be traceable to a national standard
• Calibration/verification must be performed at regular intervals, and
• Calibration/verification must be documented
CALIBRATION AND VERIFICATION
The first step in verification is to determine if the instrument is still operating within specifications before it is taken out of service for calibration. A calibration of an instrument — for example, a flowmeter — involves determining and documenting the difference between the measured and the correct value.
Traceability is accomplished by a formal comparison to a standard which is directly or indirectly related to national standards. Detected deviations between the measured value and the reference value can be corrected after the calibration by adjusting the calibration factor. A calibration protocol is issued to document the findings, and recorded for possible audits.
A substantial number of FDA warning letters are issued because remedial action after a calibration check has been considered insufficient.
Documentation about instruments and their maintenance activities has to be filed for inspector visits. Even if a flowmeter theoretically could be operated for 25 years without calibration due to its excellent safety and reliability parameters, it would most likely trigger some critical questions during an audit if no paperwork was available to prove it remained within calibration.
Calibrations are expensive, but provide very clear results for the user. Even though many instruments have proven exceptionally long-term stability which exceeds the entire lifetime of the equipment, they still have to be checked regularly to avoid legal implications.
Today, modern instruments have built-in technology to simplify compliance and verification. Several instrument vendors offer this capability, but all approach the solution in different ways.
Automatic verification is an accepted procedure. For example, Heartbeat Technology from Endress+Hauser has been tested and independently certified by the European agency TÜV. Heartbeat verification fulfills all requirements specified in ISO 9001:2008 section 7.6 and can be used interchangeably with traditional wet calibrations for traceable instrument checks.
Heartbeat Technology continuously monitors the entire signal chain for deviations within a very tight band. The failure threshold is defined by the specified accuracy of the instrument. Therefore, Heartbeat Diagnostics will trigger an alarm as soon as the sensor or instrument is no longer operating within the original specification. With automatic verification, a sensor does not have to be removed from the process until the diagnostics sound an alarm.
The entire signal chain of the instrument is analyzed for possible errors and their subsequent impact on the system and its measuring accuracy. Typically, a failure modes, effects, and diagnostic analysis (FMEDA) is used during the device design phase to identify critical components in the signal chain.
FMEDA is a systematic analysis technique to obtain failure rates, failure modes and diagnostic capability. The FMEDA technique considers:
• The functionality of each component
• The failure modes of each component
• The effect of each component failure mode on the product functionality
• The ability of any automatic diagnostics to detect the failure
• The design strength (de-rating, safety factors)
• The operational profile (environmental stress factors)
As a result, a proper safety measure has to be assigned to every critical path or component. Measures include digital signal processing and continuous loop checks with the help of internal reference components. In order for an internal component to be used as a diagnostic reference, it has to fulfill special requirements such as factory traceability and exceptional long-term stability.