How does your organization manage calibrations? Have you standardized calibration intervals at six months or one year depending on criticality? Do you use standard test points of 0, 50, 100% of full scale? Do you use a tolerance that’s 1.5 or 2 times the manufacturer’s tolerance? Years ago, most companies implemented their calibration program this way. While this approach makes it easy to induct new instruments into the calibration program and manage the calibration schedule, it’s likely to create extra work, cost your organization time and money, and may increase failures.

What is a risk-based approach to calibration, and what are the benefits? A calibration management system that gives a structured approach to instrument risk assessment, calibration program management, documentation, and corrective actions essential to regulatory compliance. The benefits from implementing this approach include, but are not limited to:

  • A focused calibration effort that concentrates on risks to product quality and public safety
  • Implementation provides a consistent approach to calibration management in line with regulatory requirements; therefore, the risk of compliance failures is reduced
  • Performing risk assessments allows calibration activities to be managed so that resources are utilized where they are most needed
  • Out of Tolerance Events are only generated for critical instruments, and are easier to complete because you have documented rationale for how the instruments impact the process

This program is based on the International Society of Pharmaceutical Engineers (ISPE) Good Automated Manufacturing Practice (GAMP) Good Practice Guide. Following the ISPE GAMP guide puts your calibration program on the road to compliance with the Food and Drug Administration’s (FDA’s) promoted risk-based approach to Good Manufacturing Practice (GMP) in the 21st Century.

The backbone of such a program depends on making the correct decisions based on reliable, accurate, and traceable information. The required information may be found in User Requirement Specifications (URS), validation protocols, and other documents that were created and approved when the manufacturing process was developed. These documents are used to meet FDA requirements based on the following decisions:

  • Whether the drug is safe and effective in its proposed use(s) and whether the benefits of the drug outweigh the risks.
  • Whether the drug’s proposed labeling is appropriate, and what it should contain.
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.

The first step is to develop an SOP that details how to complete the risk assessment and what information is required. Below is a list of the information required to complete a risk assessment, along with an example assessment process.

  • Instrument ID
  • Instrument description
  • Instrument manufacturer, model & serial number
  • Instrument range & accuracy
  • What system/process is the instrument installed in
  • Process range, operating range & tolerance
  • Instrument Criticality
  • Calibration range, test points & tolerance
  • Calibration frequency
  • Signatures of the risk assessment team members

Most of this information comes from the installed instruments and process documentation.

Next, assemble a team to perform the risk assessments, which should include:

  • Process/System Engineer – identify parameters & limits, critical steps in the process, and process tolerances. They will also approve the calibration specifications and frequencies and approve the risk assessments.
  • Calibration/Metrology Specialists – initiate & manage the risk assessment process, develop calibration specifications and frequencies, select and approve appropriate instruments to meet process requirements, set up the calibration strategy, and approve the risk assessments.
  • Quality Assurance – ensure process parameters and limits meet regulatory submission requirements, review calibration specifications and frequencies for compliance with site procedures, and approve the final risk assessments.

After assembling the team, download a report from your Computerized Maintenance Management System (CMMS) that includes the instruments for the process or system you will be assessing. It will be helpful if the report includes information pertaining to the measurement location in the process/system, the manufacturer and model number of the installed instrument, and the current calibration specifications. The risk assessment process will include answering several questions to determine the correct calibration process, limits, and frequency.

Below are some examples that could be used to determine the calibration specification

  • Instrument Criticality (may have been previously determined by an impact assessment):
    • Is the instrument used for cleaning and/or sterilization of equipment?
    • Would a failure impact the product quality or patient safety?
    • Would a failure impact the process effectiveness or other business aspect?
    • Would a failure create a safety or environmental impact?

If the answer to any of the above questions is “yes,” then the instrument is classified as critical. If the answer to all the questions was “no,” then the instrument is classified as non-critical.

Note: Some organizations may decide to implement a third category called safety critical; therefore, answering yes to the last question above would classify the instrument as safety critical.

  • Calibration range: Should be slightly wider than the process range, or alarm range if applicable, to ensure accuracy within the operating range. If an operating range has not been defined, or is unknown, calibrate the full range of the instrument.
  • Calibration test points should cover the low and high ends of the calibration range and include at least one point within the operating range.
  • Calibration tolerance should be greater than the manufacturer’s accuracy and less than the process tolerance.
  • Calibration frequency may be based on risk factors like these:
    • If a failure occurs, what’s the impact to product release?
    • If a failure occurs, how much product rework is your company willing to accept?
    • If a failure occurs, what’s the environmental impact your company is willing to accept?
    • Do you have historical data on-site for the same manufacturer and model instrument?

Through an exercise like this, your instruments will have increased accuracy and precision across the operating range, and completing out-of-tolerance investigations becomes easier now that you have a documented rationale for how the instrument impacts the process.

Additionally, some companies determine that some, if not most, of their critical instruments do not need calibration every 6 months. Some companies may opt to extend the calibration frequency of non-critical instruments to 18 to 24 months. Extending calibration frequencies is where cost savings will be most noticeable, as fewer calibration events throughout the year mean resources can focus on other activities. Remember to update any existing procedures that dictate calibration frequencies.

Another method used to extend calibration frequency is by using historical data. In this case, an initial calibration frequency is set, and after the third calibration, the data is reviewed. If the instrument passed all three calibrations without adjustment, the frequency may then be extended by 50 or 100%. Below is an example of extending the calibration frequency.

While this was a broad explanation of the subject, I hope it gets you thinking about the benefits of implementing a risk-based approach to calibration.

Joe Leuser is the Senior Manager of Metrology at Alcami Corporation, a contract development and manufacturing organization providing calibration, environmental monitoring, and pharma storage and support services to pharmaceutical and biotech companies nationwide. With a background that includes leadership roles at Commissioning Agents, Inc. and PCI, Joe has spent his career building and managing calibration programs for regulated manufacturing environments, giving him a practitioner’s view of what a risk-based approach to calibration actually requires.