Calibration of Instruments

Understanding “Calibration of Instruments” in Revised GMP Regulations

The term “calibration of instruments” appears in Article 10 (Manufacturing Management) and Article 11 (Quality Control) of the Revised GMP Regulations (enforced August 1, 2021). However, the main text of the regulations does not define this term. Instead, the definition is provided in the supplementary explanatory notes as follows:

“Calibration of instruments” refers to the process of determining the relationship between the values indicated by the instrument and the true values, using appropriate standard instruments or standard reference materials, while considering the required accuracy.

It is important to note that the main body of the regulations does not include the definition of such a fundamental term, raising questions about regulatory clarity and transparency. This approach requires users to consult supplementary documents to understand key requirements.

Critical Distinction: Calibration Does Not Include Adjustment

A crucial point to understand is that “calibration” alone does not include “adjustment” of the instrument. As stated in the definition above, “calibration” is solely the process of “determining the relationship between the values indicated by the instrument and the true values.”

The difference between the value indicated by an instrument and the true value it should indicate is called the “instrument error” (器差, kisa). If the “instrument error” exceeds the acceptable range, “adjustment” must be performed.

It is essential to recognize that “calibration” and “adjustment” are distinct processes. Strictly speaking, GMP regulations require “calibration” but do not explicitly require “adjustment.” However, in common practice, when “calibration” is performed, “adjustment” is typically performed simultaneously. Therefore, “adjustment” is generally understood to be included within “calibration” in practical implementation.

Calibration vs. Verification: Understanding the Difference

Article 53 of the Revised QMS Regulations (enforced March 26, 2021, with a transition period until March 26, 2024) contains the following requirement:

“At predetermined intervals or before use, calibration or verification shall be performed by methods traceable to measurement standards. However, when such standards do not exist, the basis for calibration or verification must be recorded.”

What is the difference between “calibration” and “verification”?

Calibration is the process of comparing an instrument with a reference standard to confirm the degree of deviation in the instrument’s indicated values. The reliability is expressed as a measure called “uncertainty.”

Verification is the process of confirming whether the deviation from a reference standard is within a specified range, such as that defined by JIS standards. Typically, a pass or fail judgment is made.

International Standard Definitions

According to TS Z 0032:2012 (ISO/IEC GUIDE 99:2007), the International Vocabulary of Metrology (VIM), the terms are defined as follows:

Calibration (校正)

An operation that, under specified conditions, in a first step, establishes a relation between the quantity values with measurement uncertainties provided by measurement standards and corresponding indications with associated measurement uncertainties and, in a second step, uses this information to establish a relation for obtaining a measurement result from an indication.

This definition emphasizes that true calibration involves a two-stage process and must include measurement uncertainty.

Verification (検証)

Provision of objective evidence that a given item fulfills specified requirements.

Example 1: Confirmation that a reference material is homogeneous with respect to the value of a quantity and measurement procedure, down to a measurement sample of mass 10 mg.

Example 2: Confirmation that a measurement system meets performance characteristics or legal requirements.

Example 3: Confirmation that a target measurement uncertainty can be met.

Adjustment (調整)

A set of operations carried out on a measuring system so that it provides prescribed indications corresponding to given values of a quantity to be measured.

Practical Implications and Best Practices

For Pharmaceutical Manufacturing (GMP Compliance)

1. Documentation Requirements: Maintain detailed records of all calibration activities, including:
   1. Date and frequency of calibration
   1. Methods used
   1. Standards employed
   1. Results obtained
   1. Actions taken when deviations exceed acceptable ranges
2. Calibration Intervals: Establish appropriate calibration intervals based on:
   1. Manufacturer recommendations
   1. Historical performance data
   1. Criticality of measurements
   1. Regulatory requirements
3. Traceability: Ensure all calibrations are traceable to national or international measurement standards through an unbroken chain of comparisons, each with stated uncertainties.

For Medical Device Manufacturing (QMS Compliance)

1. Risk-Based Approach: The Revised QMS Regulations, aligned with ISO 13485:2016, emphasize a risk-based approach to calibration and verification requirements.
2. Software Validation: When using software for measurement and monitoring equipment, validation requirements apply (Article 53, Paragraph 8 of QMS Regulations).
3. Documented Procedures: Establish and maintain documented procedures for the management of monitoring and measuring equipment.

Common Misunderstandings and Clarifications

Misunderstanding 1: “Calibration includes adjustment”

Clarification: While adjustment often accompanies calibration in practice, they are technically separate activities. Calibration determines the relationship between indicated and true values, while adjustment corrects deviations.

Misunderstanding 2: “Verification and calibration are the same”

Clarification: Calibration quantifies deviations with uncertainty, while verification makes a binary pass/fail judgment against specifications.

Misunderstanding 3: “Calibration stickers prove compliance”

Clarification: A calibration sticker indicates that calibration was performed, but compliance requires proper documentation, including calibration certificates with uncertainty statements and traceability information.

Regulatory Evolution and International Harmonization

The 2021 revisions to both GMP and QMS regulations represent Japan’s ongoing efforts to harmonize with international standards:

• GMP Regulations now incorporate concepts from ICH Q10 (Pharmaceutical Quality System) and align more closely with PIC/S GMP guidelines.
• QMS Regulations are fully harmonized with ISO 13485:2016, ensuring consistency with international medical device quality management requirements.

This harmonization facilitates global trade and mutual recognition of quality systems while maintaining patient safety as the primary objective.

Key Takeaways

1. Understand the definitions: Calibration, verification, and adjustment are distinct activities with specific meanings in regulatory contexts.
2. Maintain traceability: All measurements must be traceable to national or international standards through documented calibration chains.
3. Document thoroughly: Comprehensive records of calibration activities are essential for regulatory compliance and quality assurance.
4. Implement uncertainty analysis: Modern calibration practice requires quantification of measurement uncertainty, not just simple pass/fail judgments.
5. Regular review: Calibration programs should be reviewed periodically to ensure they remain appropriate for their intended use and comply with evolving regulatory requirements.

Additional Resources

For more detailed information on calibration and measurement standards, please refer to:

• Ministry of Economy, Trade and Industry (METI): Measurement Standards FAQ
• National Institute of Technology and Evaluation (NITE): JCSS (Japan Calibration Service System) information
• National Institute of Advanced Industrial Science and Technology (AIST): National Metrology Institute of Japan (NMIJ)

Note: This document is for informational purposes only. For specific compliance requirements, please consult the official regulations and seek professional advice as needed.