A pharmaceutical manufacturing process involves the measurement of critical parameters to ensure the performance of each step of the process. Accurate measurements are crucial to make essential decisions that have the potential to impact the health of patients. Calibration is the process of comparing the readings of an instrument or measurement device to a known and accurate reference standard. This ensures that the instrument or measurement device is providing reliable and accurate results, which is crucial in the manufacturing of pharmaceutical products.
To illustrate the importance of accurate measurement in the pharmaceutical industry, let’s consider an autoclave. This equipment sterilizes lab equipment and waste with moist heat, using pressurized steam to heat the objects up to 121°C. Laboratory glassware and even small-scale culture media are sterilized this way. If the autoclaving process is not performed effectively, it can lead to microbial contamination in the finished product.
This sterilization process is not just critical; it is also sensitive to subtle temperature changes. Even a single Celsius degree off in the temperature of the autoclave could make the process up to 25% less effective in inactivating microbes. This translates into an increased probability of contamination, which leads to an increased risk to patients.
The autoclave is just one example of how accurate measurement and calibration are essential in the pharmaceutical industry. There are many more cases where calibration is crucial to ensure pharmaceutical products’ safety, efficacy, and quality.
What is Traceability in Calibration?
Traceability is a critical aspect of the calibration process, allowing for tracking an instrument or measurement device’s calibration history. It refers to the ability to trace the calibration of a device through a documented, unbroken chain of calibrations back to a known and accurate reference standard. In the field of calibration, three levels of reference standards are commonly used to ensure traceability:
The primary standard is a reference standard directly calibrated by a national metrology institute. These institutes have the highest level of accuracy, and it is accepted without reference to other standards. These national metrology institutes establish the link with the International System of Units, located within the International Bureau of Weights and Measurements (BIPM) in France.
Secondary standards have been calibrated by an accredited calibration laboratory that has traceability to a national metrology institute. These standards are located at the correspondent National Metrological Institute.
Transfer standards are calibrated by laboratories that have traceability to secondary standards. These standards are essential for the calibration of instruments and measurement devices used in laboratories, and their traceability is vital to ensuring the accuracy and reliability of the calibration process.
Let’s take a look at the metrological traceability chain:
Figure 1. The traceability chain.
It is crucial that pharmaceutical firms use calibration services provided by accredited laboratories following international standards. The International Laboratory Accreditation Cooperation (ILAC) is the organization that assesses the conformity of calibration laboratories with ISO 17025:2005.
This international standard outlines the general requirements for the competence of testing and calibration laboratories, including the quality management system, personnel competence, and technical requirements for laboratories that perform testing or calibration. Laboratories that comply with this standard must have documented procedures for calibration and use traceable reference standards.
In particular, one of the requirements of ISO 17025:2055 is:
6.5.1: “The laboratory shall establish and maintain metrological traceability of its measurement results by means of a documented unbroken chain of calibrations, each contributing to the measurement uncertainty, linking them to an appropriate reference.”
The calibration report should always include the measurement uncertainty, details of the reference standards used in the calibration process, the exact calibration procedure and a statement that the calibration results are traceable to International standards. All of this provides assurance that the calibration results are accurate, reliable, and meet regulatory requirements.
Why is Traceability Important in Calibration?
Ensuring traceability in the calibration process is crucial to achieving accurate and reliable results from instruments and measurement devices used in developing and manufacturing pharmaceutical products. If the reference standard used in calibration is not traceable to the International System, it cannot be considered as calibration.
Traceability is essential to comply with regulatory requirements, such as the Good Manufacturing Practice (GMP) guidelines. The European GMP guidelines, for instance, require measuring devices to be calibrated and checked at defined intervals by appropriate methods:
EU GMP (Chapter 3.41)
“Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.”
This chapter of the EU GMP also states that calibration is not a one-time process, and instruments and measurement devices must be regularly calibrated to ensure they remain accurate and reliable. The calibration interval should be determined based on the instrument’s stability, the frequency of use, and the criticality of the measurement.
Non-compliance with Good Manufacturing Practices (GMPs) in a pharma company can have severe consequences, both in terms of financial losses and damage to the company’s reputation. The regulatory authorities can take action against the company, which may include issuing warning letters, fines, or even revoking the company’s license to operate. In some cases, non-compliance with GMPs can result in product recalls, which can be costly and damage the company’s reputation. That’s another reason why traceable calibration is so important.
Conclusion
The importance of traceability in calibration for pharma industry laboratories cannot be overstated. The manufacturing of pharmaceutical products relies heavily on accurate measurement and calibration to ensure that critical parameters are met and decisions that affect patients’ health are made based on reliable data. The consequences of inaccurate measurement and calibration can be disastrous, leading to product recalls, harm to patients, and damage to a company’s reputation.
Traceability, which is the ability to trace the calibration of an instrument or measurement device through a documented, unbroken chain of calibrations back to a known and accurate reference standard, is crucial in ensuring the accuracy and reliability of the calibration process. It assures that the calibration results are accurate, reliable, and meet regulatory requirements.
Pharmaceutical companies must use calibration services provided by accredited laboratories following international standards, such as the ISO 17025:2005, to ensure that their instruments and measurement devices are calibrated properly. Compliance with regulatory requirements, such as the Good Manufacturing Practice (GMP) guidelines, is also critical.
In summary, traceability in calibration is a critical process that ensures that pharmaceutical products are produced to meet the highest safety, efficacy, and quality standards. Pharmaceutical companies must take all necessary steps to ensure that their instruments and measurement devices are calibrated accurately, reliably, and with traceability to international standards. Ultimately, using accurate and reliable measurement and calibration will lead to producing high-quality pharmaceutical products, compliance with regulatory requirements, and, ultimately, benefit patients.
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