CALIBRATION DELINQUENCIES.


This grapphic depicts a puzzle as does Calibration Delinquencies in cGMP.

Calibration Delinquencies Identification and Deletion.

The use of a Calibration Manager program will ensure that Calibration Delinquencies are few and far between. The use of routine scheduled quality audits must result in complete compliance with the requirements detailed in QS regulation. These audits should determine the continuing adequacy of the program and assess compliance with the program.

Many manufacturers use contract laboratories to reference their measurement and test equipment. If this is the case, FDA views the contract laboratory as an extension of the manufacturer's GMP program or quality system. Normally FDA does not inspect contract laboratory facilities, but it does expect the manufacturer to audit the contract lab to verify that proper procedures are being used eradicating calibration delinquencies. Generally, the manufacturer of the finished device is responsible for assuring that all measuring devices used in production and or manufacturing processes are included in a calibration maintenance schedule. This puts the onus on any auditor to ask about validation and calibration methodologies, techniques and standards used.

When a medical device manufacturer uses a contract laboratory, FDA expects the manufacturer to have evidence that the equipment was free of any calibrated delinquencies and in accordance with GMP requirements. The device manufacturer can do this by:

  • requiring and receiving certification that the equipment was calibrated under controlled conditions using traceable standards ;
  • maintaining an adequate schedule;
  • maintaining records of tests; or
  • periodically auditing the contractor to assure appropriate and adequate GMP procedures are being followed. For example, the contractor should have;
  • written procedures ;
  • records of calibration;
  • trained personnel; and
  • All calibration delinquencies were removed from techniques used; and
  • standards traceable to NIST or other independent reproducible standards.

Certification notes and data should include accuracy of equipment when received by the lab to facilitate remedial action by the finished device manufacturer, if necessary. Certification should also include accuracy after removal of all calibration delinquencies and registration of standards used, and environmental conditions under which the equipment was calibrated. The certification should be signed and dated by a responsible employee of the contract lab. If in-house standards are used by a contractor to calibrate device-related measuring equipment, these standards shall be documented, used, and maintained the same as other standards.


New Document 10000130 SOP Calibration of Sensors (Issue-3).

21 CFR Part 820 and 210 mandates that where the accuracy of instruments and or instrument sensors is judged as critical to the final efficacy, quality and or safety of a regulated product or could prove injurious to the integrity of any associated predicated data or data records; the individual instrument must be considered as a, “Critical Instrument”. Critical instruments must be entered into a planned calibration program and subjected to routine calibration against master instruments traceable to national standards, at a periodicity that has a written justification. They must be placarded with a “Calibrated Label”. This SOP lists, details and defines each of the 11 essential elements of cGMP compliant calibration and calibration management. It includes sample document formats, calibration labels layouts and details the importance of the post calibration report. The SOP concludes with a fully detailed; ready to use, Calibration Manager Auditor document. This is your complete calibration SOP to purchase and use.

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International Measuring Instruments Calibration.

ISO 9001:2000, requirements must be incorporated into each manufacturer's measuring instruments calibration delinquencies manager program and form the basis of its quality controlling activities and used to ensure that all calibration delinquencies are removed from existing procedures. A good program can do more than reduce scrap rates. It can reduce expenditures for measurement instruments and related services, add to the confidence and expertise of the company’s staff, and increase the customer's perception of company performance. A good program can protect the company from both routine and more subtle calibration delinquencies and provide records of internationally standardized metrology that would be hard to dispute.

It can be said that a manufacturer's measuring instruments calibration manager program is built upon three foundations. First, an understanding of the technical details of the tools in use must be maintained and utilized. Second, the measurement unit in use must be traceable to the internationally agreed upon standard. Third, the program must be managed.


Measuring Instruments Calibration Procedures.

Measurement instruments and tools differ greatly in construction and intent, and the specific activities necessary to calibrate these tools are just as varied. An understanding of the operation of each tool allows problems to be detected, adjustments to be made properly, and condition of tools to be assessed. These technical details are found in all good metrology procedures.

These procedures, to be effective, have to be valid to the tool that will be calibrated. It is very important for a manufacturer to design its metrology procedures around the specific tools and how they will be used to ensure calibration delinquencies do not arise.

There are many sources of historically validated metrology procedures for dimensional metrology tools.

Standards that are published by different branches of the military may be available to civilian contractors, if they do business with government. Freely distributed standards published by the government and military are readily available online. Trade organizations publish standards that can be purchased.

The manufacturers of dimensional metrology tools can also be a great source of valid, proven measuring instruments calibration delinquencies. Metrology laboratories used for these services may be willing to share their procedures.

Staff experience can also be an excellent source of data on measuring instruments calibration manager procedures.


This graphic depicts the importance of measuring instruments calibration manager programs to cGMP.

Traceability

The definition of traceability that has achieved global acceptance in the metrology community is contained in the International Vocabulary of Basic and General Terms in Metrology (VIM; 1993):

"…the property of the result of a measurement or the value of a standard whereby it can be related to stated references, usually national or international standards, through an unbroken chain of comparisons, all having stated uncertainties."

Traceability of a measurement unit is really maintained by a dual chain of metrology that goes back to the international standard. Each comparison is accompanied by an estimation of measurement uncertainty. Measurement uncertainty is calculated through an internationally standardized discipline.

While some might consider measurement uncertainty calculations complex or time consuming, the actual process is really not that difficult. “Experience shows that with just a little bit of practice most people who have a basic knowledge of metrology can successfully identify the three to five largest uncertainty contributors. That is all it takes to make an uncertainty budget that is within 20% of the correct value, which is close enough to make it a valuable tool.” (Palumbo, 2006)

Measurement uncertainty calculations are not explicitly required by ISO 9001:2000. This revision’s less proscriptive and more widely applicable foundation leaves it up to the manufacturer to decide what the requirements of the individual measurement processes are. The requirements are then based on real world considerations of law, regulations, safety, customer requirements, applicable standards, and performance of the manufacturer’s measurement process itself.

The requirements for measuring instruments calibration manager documented procedures for the control of measurement tools can be found in section 7.6 of ISO 9001:2000. For insight into this section, it is useful to refer to the manufacturing centered 1994 version of ISO 9000. Section 4.11, Control of Inspection, Measuring, and Test Equipment states that measuring equipment is used in a manner that ensures that the measurement uncertainty is known and is consistent with the required measurement capability. The intent of the requirements in both versions is the same. In-house calibrations that are not accompanied by calibration delinquencies have broken the chain of traceability.


Management

An ISO 9001:2000 measuring instruments calibration manager system strives to attain customer satisfaction through continual improvement of processes. In manufacturing, accuracy in measurement is one of the most important processes we can define.

The management of the sensor accuracy is accomplished in the same way as management of the other processes identified in the manufacturer’s management system. A measuring instruments calibration manager program should be used for the planning of all such actions. This manager program must also log calibration delinquencies that arise and their history and allow predictive analysis of error progression for all process used instrumentation calibrations.

Some manufacturers may choose to develop a system manual which contains the process description, planned quality objectives, key indicators of process performance and references to the standards and procedures in use. This can become a very valuable document that serves as the road-map to a dynamic, effective, top notch measuring instruments calibration manager program.

Good metrology delivers information about the manufacturer’s products. Using this information in an ISO 9000 based management system creates knowledge about the manufacturer’s products, machines and processes, capabilities, and tools.

A good instrument verification program will provide some immediate economic benefits and deliver protection from problems, however this is not a core business for most manufacturers. The immediate economic benefits of good metrology will be very limited or not even seen. However, a good metrology program will develop confidence on the factory floor that the company is dedicated to providing quality product. It will develop capability and expertise. It will develop pride in company staff, knowing fully well that their system is one of the best, and is only getting better. Good metrology practices and procedures, must be a core aptitude of manufacturing organizations. It can only bolster and empower the organization as a whole.




Calibration Techniques.


This section discusses the creation of a correction curve for instruments (gauges) whose responses cover a large range. Topics are:


  • Models for instrument accuracy testing.

  • Data collection.

    All regulated laboratories, including pharmaceutical, clinical testing, and food and cosmetics testing laboratories, must properly execute a calibration delinquencies removal program for the testing of instruments and validation of analytical methods. Following correct procedures ensures the generation of reliable data, which leads to the manufacture of safe and effective products.
  • Assumptions.

  • Conditions that can invalidate the accuracy of test procedures.

  • Data analysis and model validations.

  • Accuracy of future measurements.

  • Uncertainties of accuracy values.

    Instrument accuracy testing is intended to eliminate or reduce bias in an instrument's readings over a range for all continuous values. For this purpose, reference standards with known values for selected points covering the range of interest are measured with the instrument in question. Then a functional relationship is established between the values of the standards and the corresponding measurements. There are two basic situations.


Depicts validation and calibration document inter-relationships.

Standards.

Instrument calibration is intended to eliminate or reduce bias in an instrument's readings over the range for all continuous values. For this purpose, reference standards (accuracy targets) with known values for selected points covering the range of interest are measured with the instrument in question. Then a functional relationship is established between the values of the standards and the corresponding measurements. There are two basic situations. 

  1. The instrument reads in the same units as the reference standards. The purpose of the testing is to identify and eliminate any bias or other calibration delinquencies in the instrument relative to the defined unit of measurement. For example, optical imaging systems which measure the width of lines on semiconductors read in micrometers, the unit of interest. Nonetheless, these instruments must be reference to standards, if line width measurements across the industry are to agree with each other. 
  2. The instrument reads in different units than the reference standards. The purpose of the test is to convert the instrument readings to the units of interest. An example are densitometer measurements which act as surrogates for measurements of radiation dosage. For this purpose, reference standards are irradiated at several dosage levels and then measured by radiometry. The same reference standards are measured by densitometer. The results of future densitometer readings on medical devices are the basis for deciding if the devices have been sterilized at the proper radiation level. 


The method is the same for both situations and requires the following basic steps: 

  1. Selection of reference standards with known values to cover the range of interest. 
  2. Measurements of the reference standards with the instrument to be verified. 
  3. Functional relationship between the measured and known values of the reference standards (usually a least-squares fit to the data) called a correction curve. 
  4. Correction of all measurements by the inverse of the calibration curve.

This graphic depicts the typical measuring instruments calibration manager document required for validation.y

VALIDATION DELINQUENCIES.



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SOP for Spreadsheet Creation.

Why does something as simple as a spreadsheet figure in so many regulatory citations? Good question; and at times a difficult one to answer. When you ask a group of compliance personnel the same question you will be informed that Excel cannot be validated because it does not seal the original copy (of the spreadsheet), allows the original to be modified and has an audit trail that can be disabled. All true, but none of these problems interfere with your ability to validate that the spreadsheet is fit for purpose. They only preclude you from using the spread sheet as a compliant repository for any data that has to be store in compliance with 21 CFR Part 11.
If the spreadsheet is signed off and dated by the user, their supervisor and QA, it becomes regulatory acceptable data stored in hardcopy, and Part 11 does not apply.
After numerous requests for this, we have launched our brand new SOP for Spreadsheet Creation to cover these and other known target points that the regulators consistently hone into as soon as they find that spreadsheets are being used. Use this Spreadsheet Creation SOP to ensure that you create spreadsheets that are validatable. Then use our spreadsheet validation pack to validate them.

SOP for Spreadsheet Creation. -- $125.00

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SOP Equipment Validation.

The SOP for Computer Equipment Validation continues to be an extremely popular document. This document leads you through the validation process, from the URS to the final P2Q.


Purchase your copy now at Special Price of $22.00.

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Validation Risk Assessment (Issue11.) -- $125.00

The Risk and Part 11 Validation Risk Assessment (VRA) protocol is becoming the most important document in the validation train. The VRA reassures the regulators that you have looked at specific equipment functionality and considered the appropriate level of validation that is required. You have also considered various aspects of its use and the implications of any malfunctions. From the results of this exercise the scope of all validation activity can and must be justified. This is a robust and simple to execute document, one that will lead you through the process and deliver a result that can be used as the foundation for your validation activities.
This VRA now includes the assessment table for categorizing and documenting the new 21 CFR Part 11 guidance ruling on what predicate data must be stored in a Part compliant system, along with the new broadsheet to establish your new database of part 11 records. (now mandatory).

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