Environmental control has a direct impact on aseptic manufacturing and the prevention of drug deterioration in pharmaceutical facilities throughout the production and distribution chain. Proper and effective monitoring is necessary to prove that specified conditions have been achieved. Failure to prove adequate control can lead to expensive consequences. (See http://www.veriteq.com/avoid-fda-483s/avoid_and_respond_to_fda_483s-wp.htm for a summary how to respond to FDA observations.)
Whether you need to ensure that positive pressure is maintained in clean rooms, or that temperature and RH remain in ranges that maintain pharmaceuticals’ efficacy, or oxygen levels in the air near stored liquid nitrogen are not threatening staff safety, or drug stability chambers are validated—you are talking about measurements that involve sensors. Sensors—all sensors—will drift over time. That is why all instruments for monitoring environmental conditions must be calibrated and then re-calibrated at regular intervals.
All pharmaceutical quality managers know that calibration is not a nicety and it is not optional. It is required to ensure product quality and for full FDA compliance. That said, all calibrations are not equal, nor are calibrations a panacea for instrumentation that is not up to the accuracy needed to provide early warning of environmental problems or the recording of correct data.
Five Guidelines for Calibration and Instrument Sourcing
1. Use Best Practice Laboratories: Every environmental monitoring instrument that you purchase has already been calibrated by the manufacturer before it is shipped to your facility, and it will be delivered with a certificate of calibration (example in Figure 1).
Your due diligence in sourcing environmental monitoring systems can determine whether they will meet your needs for accurate and reliable measurements. Begin by asking if the instrument manufacturer meets best practices for calibration. For example, do they follow ISO 17025 standards? Are they also an accredited laboratory?
Initially introduced by the International Standards Organization (ISO) in 1999, the ISO 17025 quality standard was specifically written for calibration facilities going beyond the ISO 9000 quality standard to also compel calibration laboratories to demonstrate competence and to apply their documented quality management systems. American Association for Laboratory Accreditation (A2LA), National Laboratory Voluntary Accreditation Program (NVLAP), Laboratory Accreditation Bureau, and similar calibration accreditation bodies certify that calibration facilities meet the requirements for ISO 17025 standards.
A declaration of ISO 17025 implies the use of a quality system designed to improve the ability to consistently produce valid results. An accredited laboratory has been recognized by a third party, confirming the lab’s competence and that it operates under a documented quality system. Accreditation means the lab has successfully passed an audit and becomes an accredited ISO 17025 laboratory.
2. Start with Accurate Monitoring Instruments: No matter how sophisticated the calibration laboratory, it cannot compensate for the inherent performance limits of the instruments it calibrates. For example, an instrument that has a published accuracy of ±1°C may be calibrated in an ISO 17025-accredited laboratory with a ‘best uncertainty’ of ±0.02°C. In this scenario, the calibration facility will not be able to improve the specification of the instrument to better than ±1°C. No amount of calibration or re-calibration will improve the accuracy of an instrument as a measuring device.
3. Understand the Meaning of NIST: Have you ever asked or heard the question: “Is the instrument calibration NIST traceable?” If you are satisfied when the answer is “yes” and look no further, there is a major problem. Used on its own, this phrase does a disservice to a quality system because “NIST traceable” says nothing about instrument performance. It merely means that the reference equipment used to calibrate a monitoring instrument was traced, through a lineage of reference standards, to an instrument that was calibrated by NIST (National Institute of Standards and Technology). It has no relationship to specified accuracy but rather, only describes one fact about the calibration equipment.
4. Calibrate for the Operating Environment: Calibrations should incorporate test points that reflect the range of the parameters that the instrument is expected to measure. This definitively proves the performance of the instrument.
In many cases instrument manufacturers provide empirically derived valid data about the performance of their devices over a wide range of conditions. This is not in dispute, but when you need to prove instrument performance to industry regulators, there is nothing like a calibration document showing that the instrument was tested throughout the range of its expected operating conditions.
5. Ensure Correct Data: Last, but certainly not least, how do know your measuring system will provide accurate data until the next calibration? According to most instrument manufacturer’s specifications, you don’t.
It is a curious yet widespread practice of most monitoring instrument manufacturers that they do not stipulate that the instruments will remain in spec until the time of the next calibration. In other words, you have no ability to gauge the stability of the monitoring instrument over time. If you are using such a monitoring instrument, i.e. one where the stability is not stated by the manufacturer, you may be introducing a wildcard into your quality system. If such monitoring instruments are found to be out of specification at the time of re-calibration, you may have a problem.
By using historical knowledge of instrument behavior, the manufacturer of the measuring instruments can quantify the characteristics of their systems over a time interval. It is not unreasonable to ask: what will the instrument accuracy be six, nine or even twelve months later? The best advice is look for a source that will state the system accuracy over time, which is to say that you know what the maximum drift should be when it’s time to recalibrate. All sensors do drift from their initial calibration specifications, but the manufacturer can study this inevitable drift and specify it such that calibration intervals can be clearly defined by the user. This increases the likelihood that “as found” calibration data (before recalibration) will show accuracy to be within specifications.
In summary, quality managers know that instrument calibration is a mandatory part of managing quality. However, many may be unaware of how integral calibration practices are to making a quality system work successfully. Without a calibration program that addresses laboratory methods, monitoring instrument accuracy and stability and measurement range, pharmaceutical quality managers are taking unnecessary risks. Best practice calibration methods can prepare a measuring system for the intended application and avoid the risk of compromising product quality and incurring significant financial loss. Furthermore, you can shore up your quality system for internal and external (21 CFR 820, 211, 58…) review by integrating best practice calibration procedures. Knowledge about the stability of the measuring system over time can prevent the unintended consequences when documentation is reviewed in a customer or FDA audit.
About the Author
Ken Appel is Manager Regulated Markets for Veriteq, a Vaisala company (www.vaisala.com/veriteq), which provides environmental monitoring systems for temperature, humidity and other critical variables in controlled environments for pharmaceutical and biotech manufacturers, research laboratories, and other critical life science storage applications. Questions can be forwarded to Mr. Appel at firstname.lastname@example.org, 800–683–8374.