4.4 Measurement Equipment Calibration Program

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?

Do the CGMP regulations require equipment to be labeled with calibration dates? Do the regulations distinguish critical from noncritical equipment for this purpose?

Has the "zero" calibration step, that uses room air, for the Servomex Model 570A oxygen analyzer been discontinued? If so, when should a firm implement the revised calibration procedure?

Is it acceptable for a manufacturer to replace faulty or out of calibration instrumentation with "spare/backup" instruments that have been previously calibrated but stored at a remote location?

The USP states that a balance needs a Measurement Uncertainty (MU) that doesn't exceed 0.001. Would a balance having an MU of 0.00149 meet the specification? What if a firm's numerical analysis SOP states to round from one number past the reported value (i.e., drop the nine and round based on the four)?

How often should dissolution test apparatuses be calibrated when they are used with both baskets and paddles?

How should USP dissolution calibrators be stored?

What are the requirements for the calibration of vacuum gauges?

If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?

Reference: 
21 CFR 211.22(a & b), Responsibilities of quality control unit, 
21 CFR 211.160(b), General requirements [Subpart I—Laboratory Controls]; 
21 CFR 165, Testing and release for distribution (sic); 
Draft Guidance for Industry: Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production, 9/30/98; 
21 CFR 211.194, Laboratory records

There are a number of possible scenarios under this question. Under CGMP, FDA would expect the contract laboratory to have a quality control unit. The lab's QC unit has the CGMP responsibility to ensure the analytical results obtained are accurate for the tested material. This means the contract laboratory needs to investigate any OOS result with the purpose of ascertaining such accuracy. This would be accomplished by ensuring that personnel performed the tests properly using: (1) The current validated analytical procedure; (2) correct reagents and reference standards; and, (3) equipment that has been properly maintained and calibrated.

There are basically two possible results of the lab's investigation.

1) If the lab determines the analyst made an error, or that instrument malfunction occurred, the test results may be invalidated. The analysis would be re-run according to the approved analytical method. The re-run test results would be considered the original results, and these results would be reported to the manufacturer. The lab does not have a CGMP obligation to report the initial (invalidated) results to the manufacturer; however, the lab must, per 211.194, retain the records pertaining to those initial results.

2) If the laboratory determines that there was no analyst error, and that no instrument malfunction occurred, then the results must be considered accurate and reported to the pharmaceutical manufacturer.

In the event of outcome number two, the pharmaceutical manufacturer would have analytical results indicating the material does not meet its specifications. Under CGMP, an investigation must take place. The manufacturer is responsible for investigating the production process to determine if any mistakes were made--things to consider could include charge-in of components, mixing times, and quality of components. Storage conditions of the analyzed material, and the sampling method used also need to be reviewed to ascertain whether the tested material might not have been representative of the batch.

If the manufacturer's investigation fails to find a cause, it might also consider whether the contract laboratory is suspect (i.e., if perhaps the lab made an unrecognized error.) The CGMPs do not, however, explicitly require the manufacturer to extend its investigation to the lab's operations. However, it is considered CGMP for manufacturers to qualify their contract laboratories.  At comment paragraph 94 of the September 29, 1978 CGMP revisions, 43 FR 45034, the agency said "[a] manufacturer does have a responsibility, however, to see that the outside laboratory used is qualified to do the work and that the work is performed satisfactorily." 

As part of its investigation, the manufacturer might take the opportunity to requalify the contract laboratory, or may consider changing contract laboratories. Retesting could also be part of this process.

It must be stressed that in this situation the manufacturer has information that the batch does not meet its quality standards, and unless that information can be invalidated, it must be used to reach a batch disposition decision, namely, whether to destroy the batch, or reprocess it to bring it into compliance. 

Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999.
This same text is also reprinted in Framework sections 1.1, 4.3, 5.2, 5.5, 6.4, and 7.2.

Do the CGMP regulations require equipment to be labeled with calibration dates? Do the regulations distinguish critical from noncritical equipment for this purpose?

Reference: 
21 CFR 211.67, Equipment cleaning and maintenance; 
211.68(a), Automatic, mechanical, and electronic, equipment;
211.160(b)(4), General requirements [Laboratory Controls]; 
211.105 Equipment identification.

No and no. The CGMP regulations do not require that each piece of equipment bear status labeling as to its state of calibration or maintenance. However, per 211.67, 211.68, and 211.160, equipment must be calibrated and/or maintained according to an established schedule, and records must be kept documenting such activities.

The regulations do not distinguish critical from noncritical equipment for calibration and maintenance purposes. However, the need for calibrating a given piece of equipment depends on its function. In general, things that measure materials warrant calibration. In addition, the 1978 preamble to the CGMP regulations states that 211.68(a) is intended to control equipment having an effect on product quality. Prudence dictates this be interpreted broadly. Equipment not requiring calibration/maintenance need not be tracked or included in the firm's calibration/maintenance program.

During an inspection a firm should be able to document when a specific piece of equipment was last calibrated/maintained, the results or action, and when its next calibration/maintenance is scheduled. The absence of such documentation is a CGMP deviation. While the absence of a calibration/maintenance tag is not objectionable, the presence of a calibration/ maintenance tag alone should not be assumed to satisfy regulatory demands, and the supporting documentation should be audited. The firm should also be able to support its decision to not include a particular piece of equipment in the calibration/maintenance program.

Don't confuse use of calibration tags with the CGMP requirement, at section 211.105, that major equipment be identified with a distinctive number or code that is recorded in batch records. This identification requirement is intended to help document which pieces of equipment were used to make which batches of drug product. 

Contact for further information: Brian Hasselbalch, HFD-325, (301)594-0098: e-mail: hasselbalchb@cder.fda.gov

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 4) December, 1997.
This same text is also reprinted in framework section 4.3.

Has the "zero" calibration step, that uses room air, for the Servomex Model 570A oxygen analyzer been discontinued? If so, when should a firm implement the revised calibration procedure?

Reference:
211.160(b)(4), General requirements and 
211.165(e), Testing and release for distribution, [Subpart I - Laboratory Controls].

Yes. The procedure known as the "U.S. Instruction Manual for Servomex Model 570A Oxygen Analyzer" (Addendum) has been discontinued, through a joint effort between the Servomex Company and FDA, effective October 9, 1997, Rev. 5. Servomex intends to notify its customers regarding this change.

Therefore, any firm using a Servomex Model 570A and calibrating the analyzer via the Addendum needs to stop using this method immediately and begin calibrating the analyzer according to the original or new manual. 

Calibration using the Addendum would be an appropriate FDA 483 item because the method is not scientifically sound.

The revised calibration procedure discussed under Section 6.0, "Calibrating the Model 570A," and under Section 3.3, "Calibration for Oxygen U.S.P. Verification" (new section), in the new manual calls for the use of high purity nitrogen with a minimum potency of 99.9% for the "zero" step, and oxygen with a minimum potency of 99.2% for the "span" step. This method is scientifically sound.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 4) December, 1997.

Is it acceptable for a manufacturer to replace faulty or out of calibration instrumentation with "spare/backup" instruments that have been previously calibrated but stored at a remote location?

Reference: 
21 CFR 211.160(b)(4), General requirements, Subpart I, Laboratory Controls.

Yes, provided the replacement instruments remain within calibration, meet established specifications, and haven't been stored longer than the established calibration interval.

The heart of the issue is equipment suitability. Let us assume that the spare instrument is, first of all, the same make and model as what it is supposed to replace, thus ensuring that performance characteristics of the two are the same and the analytical method at hand is not modified. If that's the case, then the spare instrument may be stored anywhere storage conditions don't adversely affect its performance (reliability, accuracy and precision).

Before any lab instrument is put into use, the CGMP regulations require that the firm ensure it is within calibration specifications.  If the "spare" instrument may drift out of calibration during storage, as might be the case if it has moving parts, then we would expect the firm to recalibrate the instrument before putting it into service. Remember that some instruments are so delicate that just moving them from one place to another causes them to go out of calibration. 

Finally, section 211.160(b) of the CGMP regulations requires firms to calibrate laboratory instrumentation at appropriate intervals according to a written program. If the storage period for the "spare" in question exceeded that interval, we would expect firms to re-calibrate the instrument prior to use.

Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.
This text is also reprinted in Framework section 4.3.

The USP states that a balance needs a Measurement Uncertainty (MU) that doesn't exceed 0.001. Would a balance having an MU of 0.00149 meet the specification? What if a firm's numerical analysis SOP states to round from one number past the reported value (i.e., drop the nine and round based on the four)?

Reference: 
21 CFR 211.160(b)(4) as in the question above; 
USP 23 <43> Weights and Balances, page 1680.

USP 23 states ±0.1% accuracy and gives an example of 50 mg ± 50 ug as acceptable. The above question reflects that clarification is needed in two areas, 1) the meaning of significant figures, and 2) measurement uncertainty.

For a number 0.001 to be significant at 0.001, the uncertainty of the final digit is ±.0005; i.e. the actual figure has a potential true value of anywhere from 0.0005 to 0.0015. The MU of 0.00149 cited would meet the specification because it falls within the limits stated. The final 2 digits of 49 given in the question may or may not be significant. The USP gives the minimum acceptable limits of precision; greater precision is acceptable. However, this leads to the question of the meaning of the final 2 digits given. If they are not significant figures, then they should not be reported. It's a little like giving a person's height to 1/64 inch, but taking the measurement using a yardstick graduated in inches. You may have confidence in that measurement to within ±½ inch, no more. For more precision, another measuring device capable of greater accuracy would be needed.

A balance exhibiting a reading of 0.001 thus has a potential uncertainty range of 0.0005 to 0.0015. The mass used for calibration should be traceable to a national standard or a mass with an uncertainty statement. Traceable means an unbroken chain of measurements relating to a national or other acceptable standard. For the US, the national standard weights are stored under controlled conditions at the National Institute of Standards and Technology (NIST) in Gaithersburg, MD.

Generally, an electronic balance has linearity and precision compared with internal weights, and calibration is done with a traceable standard. The accuracy is often compared to traceable reference standards kept with the balance on a daily or weekly basis, and certified biennially. While the USP may specify an accuracy of 0.1%, throughout the pharmaceutical industry you generally find the balances in use capable of greater accuracy.

Common practice is to weigh a pharmaceutical sample on a transfer vessel (a weighing boat or weighing paper), transfer the sample to the preparation vessel (volumetric flask, beaker etc.), then weigh the empty transfer vessel. The difference in weights is the sample weight. It is important to note that this differential weighing tends to cancel any gross errors in the balance accuracy, as determined by the calibration with the reference weight. That is, balance weight errors will be of the same magnitude on the same side of the ± uncertainty.

Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov 

Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.

How often should dissolution test apparatuses be calibrated when they are used with both baskets and paddles?

References: 
21 CFR 211.160(b)(4) General Requirements, Subpart I, Laboratory Controls; 
USP 23, Section 711, Dissolution

The CGMP regulations call for apparatus calibration at suitable intervals. Although specific time periods are not given, apparatuses should be calibrated every six months as part of a firm's routine SOP. This calibration requires testing with both baskets and paddles at both 50 and 100 rpm with both USP Calibrator Tablets, Prednisone Tablets and Salicylic Acid Tablets.  The only exception is if a company uses either baskets or paddles exclusively. In those rare instances, the firm only needs to calibrate with both Calibrator Tablets at both speeds and the single stirring element that it uses. In case of any event that might change operating characteristics of an apparatus, such as construction or moving it, it should be calibrated as described above prior to use.

Contact for further info: Bob Rippere, HFD-354, phone (301)594-0104, e-mail: rippereb@cder.fda.gov .

Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 2), June, 1996.

How should USP dissolution calibrators be stored?

Reference: 
21 CFR 211.160(b), General Controls, Laboratory; and 
"Calibration of Dissolution Apparatuses 1 and 2--What To Do When Your Equipment Fails," Pharmacopeial Forum 20(6), November-December 1994.

The only lots of USP Calibrator Tablets that have official status are Prednisone Tablets, Lot K, and Salicylic Acid Tablets, Lot  M. All previous lots have expired. Both official lots are labeled to "Keep container tightly closed. Store in a desiccator or in a dry place at room temperature." It has been found that high humidity is the primary cause of instability of both calibrator tablets.

Contact for further info: Bob Rippere, HFD-354, phone (301)594-0104, e-mail: rippereb@cder.fda.gov .

Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 2), June, 1996.

What are the requirements for the calibration of vacuum gauges?

Reference: 
21 CFR 211.68 (Automatic, mechanical, and electronic equipment).

Vacuum gauges used during the evacuation of high pressure cylinders require a daily "calibration." This simple calibration consists of an inspection of the gauge prior to the pulling of a vacuum, and with no pressure on the line. The needle should return to "zero"; if not, then an adjustment is required. If the needle cannot be adjusted and returned to zero, then the gauge should be replaced.

In addition, a firm is required to establish written calibration procedures describing their process and should document that the calibration was performed.