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Calibration and Qualification in Analytical Laboratories

With examples from planning to reporting

Recorded, available at any time

 

Analytical Instrument Qualification According to USP <1058>

With SOPs, Templates and Examples for Easy Implementation

Recorded, available at any time 

 

Qualification and Calibration of Stability Chambers

Learn how to select, conduct and document the right test parameters and conditions

Recorded, available at any time

 

Validation of Automated Laboratory Systems

Recorded, available at any time 

 

Validation of Software and Computer Systems in Analytical Laboratories

Recorded, available at any time

 

Understanding the Updated USP Chapters 232/233 for Metal Impurities

With SOPs and Case Studies for Easy Implementation

August 11, 2011

 

Validation of Bioanalytical Methods and Procedures

Conduct and Document for Efficiency and FDA&EMA Compliance

June 30, 2011

 

FDA Compliance for Biopharmaceutical Laboratories

Become familiar with FDA regulations and get tool kits for implementation

June 16, 2011

 

Learning from Recent Warning Letters Related to GMP Laboratory Controls

For Preparation of FDA and International GMP Laboratory Inspections

Recorded, available at any time 

 

Transfer of Analytical Procedures According to the New USP Chapter <1224>

With SOPs, templates and examples for easy implementation

Recorded, available at any time 

 

Laboratory Equipment Qualification and System Validation

Question and Answers

Author: Dr. Ludwig Huber

Frequent speaker and chair person at FDA, ISPE, PDA, USP. IVT, and GAMP conferences and workshops

Here Ludwig Huber (right) in the Q&A Discussion Session on Laboratory Compliance at an ISPE/FDA Beijing University Conference with Nick Buhay, Acting Director in FDA/CDER's Division of Manufacturing and Product Quality

For Dr. Huber's connection with the FDA, click here

.

Q: What is the difference between Performance Qualification (PQ) and Performance Verification (PV)?

PQ is the last Q in the 4Q model for equipment qualification (see figure below). The qualification terminology has first been described by the pharmaceutical industry validation experts for manufacturing equipment and has been used in official documents such EU-GMP Annex 15 and ICH Q7. Later on the 4Q approach has also been formally introduced to the analytical laboratory through the USP Chapter <1058>: Analytical Instrument Qualification and Equipment Qualification is frequently referenced in FDA warinng letters.. PQ means checking that the complete system works as intended for a specific application, e.g., an HPLC system is not only comprising equipment hardware but also columns, reference standards and the computer hardware and software controlling the system. PQ should be checked with a standard that is similar to real samples and the check should be  frequently. According to USP <1058> in HPC quality control analysis PQ can be substituted by system suitability testing. The meaning of PQ is different from PV.

The 4Q model for equipment qualification

 

The term Performance Verification (PV)  comes more from the ISO and ASTM world, such as ISO 9000, ISO 17025 and ASTM E2500. The task of PV is in line with OQ from the 4Q model and basically means that the equipment (hardware) performs as specified by the user. The similarity is demonstrated in the figure below that compare PV as defined in ISI/IEC Guide 2 with OQ as defined in Pharma publications. The bottom line is that both terms OQ and PV are used interchangeably for the same  task..

The best statement I have seen comes from the GAMP® Good Practice Guide for Laboratory Computerized Systems (Version 2): "Whatever terminology is used for verification activity (could also state: qualification activity), the overwriting requirement is that the regulated organization can demonstrate that the system is compliant and fit for intended use”

Performance Verification vs. Operational Qualification

 

Q: It is my understanding that USP General Chapters above <1000> are
recommendations and are do not carry the same weight as those below 1000 they are not "official". The seminar on (AIQ) <1058> sounds as though it is more than just a recommendation. Please comment

Thanks for your comment. You are right, general chapters from 1000 - 1999
are recommendations. as I have been told by the Chairman of the <1058>
chapter, they will become mandatory for any mononograph that requires to
qualify instruments before running a sample. In light of this it is a good
recommendation to use always the same approach for instrument qualification,
but no question, the amount of testing and documentation will vary with the
complexity of the instrument and the criticality of the application, and USP
leaves a lot of room for interpretation.
Also FDA typically asks for equipment or instrument qualification, and
inspectors are quite familiar with the USP approach, so this also makes
sense. If the seminar description did give the impression, that USP 1058
will always be mandatory, then I am sorry for this, nevertheless I would
follow the approach, just to stop the endless discussions.

Q: Since firmware is typically part of the equipment and is OQ'd by the supplier, does the supplier typically OQ the firmware as part of a maintenance firmware upgrade?

Firmware is qualified as part of hardware qualification. I don't believe that such qualification is part of a maintenance firmware upgrade. But the vendor should give you recommendation if  hardware re-qualification is necessary after a firmware update. This is only necessary the firmware update can have an impact on the hardware performance.

Q: We have a global LIMS system. At a site level, certain instruments are linked to the LIMS. If we have to move the hosting of the global LIMS system, what is the validation/qualification requirements for the LIMS (global and site levels) and the linked instruments?

Most important is to test the communication when you move the hosting of the global LIMS.

Q: How do you handle shut down of equipment for maintenance and or removal? I worry about chemical and biological contamination of personnel handling the shut down and removal

This should be covered by cleaning procedures associated with safety precautions. This is not covered by USP <1058>.

Q: How does the USP defined IOPQ definition relate to the current industry and FDA view of verification testing (as per current ISPE initiative)

To be honest I don't think there is a conflict. All documents recommend to do some kind of testing when equipment is installed with to make sure that the equipment works in the intended environment. Process equipment that is used for a For laboratory equipment that is always used for specific processes, can be be fully tested with PQ. Analytical instrument most frequently is used for several applications and analytical methods. This makes it more practical to verify first that the instrument meets specifications which is QO. I am note aware that the FDA has a different view. And ISPE has published a Good Practice Guide for validation of laboratory systems. The guide is also based on IQ/OQ/PQ

Q: Why do we need to qualify the instrument if we do system suitability testing anyway

There are a couple of reasons. I would recommend to look at the presentation from FDA’s Dr. Nasr. You can download it from the reference website. On slide 21 of that presentation you can find some reasons, for example, he states that SST may not guarantee error free chromatography and he also gives a scientific reference for this, for example SST may not be comprehensive enough to detect critical HPLC system performance problems, because you just don’t measure all parameters that are critical for analysis. An other reason is that ensuring independent and objective qualification of critical system components will aid in the development of robust and transferable methods.

Q: Is the USP standard available on the Labcompliance website

No, all these chapters are copy-right protected by USP. You can get it from www.usp.org

Q: The standard says, users of commercial systems should check the vendors quality system. Is an ISO 9000 certification enough proof for this?

For equipment hardware yes, for complex software is it not enough. It depends on complexity and the risk the software or computer system has on product quality

Q: USP standards are for US FDA regulated environments. What about Europe.

The 4Q model is also well established and expected to be implemented also in Europe. There is an Annex 15 to the European GMPs: Validation and qualification. This document also requires all four phases for equipment qualification.

Q: If calibration is expired on a validated system is it considered invalidated. If so, then what testing needs to be done to bring it back to the validated state.

  1. Yes, it is considered to be invalidated
  2. Go back and repeat the initial calibration

Q It was implied that determination of system suitability and monitoring of accuracy through a control sample may not be sufficient to fulfill PQ. It would seem to me that a properly designed SS would show consistency of operational parameters. For instance in a chromatographic system retention within a specified window along with resolution and/or efficiency would demonstrate that flow rate, temperature, detector parameters were all functioning consistently. Can a well designed SS fulfill PQ requirements? If not, what more may be needed?

I had hoped that I made this clear that a well designed SST test can be sufficient for PQ, only the first USP draft said the opposite, but it has been corrected. It really depends on how you design the SST runs. E.g., if you need quantitative trace analysis it is not sufficient to check precision of amounts at 'some' amounts, you either need to make the test at the relevant amount in the LOQ range or you need to have a additional PQ test to re-test the baseline noise.

Q: You discussed very much the implementation of the USP validation approach in a GMP kind of environment, which tends to require much more in depth validation. Do you have any insights into implementation in a GLP environment. The GLP guidelines in general tend to be very vague about what validation entails, and in my experience the level of validation expected tends to be less.

I fully agree, but it is really nowhere written. This goes back to risk based compliance. Some companies call this "GLP Light". Example for less qualification are:
* Less frequent PQ
* Less frequent OQ requalification
* less detailed vendor assessment

But there is no official matrix

Q: Why is the GAMP terminology and way of categorizing instruments not used? Why is there not a direct link between the GAMP and the UPS categorization of instruments?

This seminar was limited to USP AIQ. Bringing in a discussion on the GAMP Lab Systems Validation Guide and its 7 categories would not fit into the scope and time frame of this seminar. Seminar 141 Validation of Automated Laboratory Systems is just on the comparison USP vs. GAMP. Check www.labcompliance.com/seminars/audio141

Q: This question is related to my previous question:
Calibration is expired on a validated system and after some time there is a new platform (hardware)added to that system, what document needs to be initiated.

  1. Open a Deviation: Stating calibration is past due, then calibrate the system

  2. Initiate Change control to capture hardware change or is there any suggestion to handle this type of situations

Your recommendation 2) is perfect
The risk assessment may or may nor trigger a new calibration.

Q: Two items are often mixed up: OQ and PQ.
Can you line out the main difference between these?
From my point of view the OQ is covered by the PQ if the PQ is successfully performed, because one cannot bring a PQ to an end if the device would not work well.

Typically OQ verified specifications of the instrument (e.g., gradient accuracy of a pump). PQ is method specific, e.g./ checks the precision of your compound, here in a gradient run. If you have a good OQ that verifies the gradient precision from e.g., 1-99 %, you have good assurance that the system will pass PQ tests, not only for one application, but for all gradient analyses. For some instruments such as a balance OQ and PQ tests are very much the same, so you can combine them.

Q: Regarding the validation of analytical software (e.g., ChemStation) - is it preferable to purchase the computer with software installed and validated by manufacturer vs. installing software on existing computer and validating on site?

This is not a compliance but a business question. Most likely you get sooner to your analysis results if you purchase preloaded software on pre-tested hardware and the vendor provides IQ and OQ, but it may be more expensive.

Q: You said in a seminar that there will be a special seminar to go through examples for various qualification deliverables, will that seminar include all documents as hand-outs and if yes, when will that be?

In the meantime the seminar has been delivered and comes with a full sent of qualification documents. For details, click here .

Q: How frequently should we re-qualify analytical equipment

Frequency will depend on manufacturer’s recommendations, required performance, degree of use, nature of use and instrument history. For a typical HPLC instrument we recommend once a year.

Q: Is there any difference when we qualify new versus existing systems

Be aware, the question will never be: is this a new or an old system. The question will be: how did you make sure that the instrument performs as intended. This means all documentation should be available as foe new systems. The process is different, for example, you don't formally define requirement specifications but describe which functions the instrument is using. 

Q: How long should validation documentation be retained

Validation documents should be retained as long as the regulated data or records that have been generated by the system.

Q GAMP has published a good practices document on “Validation of laboratory computer systems”. The new USP draft also says something about software and computer systems. Is there a difference between both documents and if so which guide should we follow?

It’s interesting that both have been published at around the same time. I could not find any conflicting statements in both. The USP chapter <1058> is very generic and includes all types of instruments. The GAMP guide is more focused on automated systems. I would recommend to look at both and use the GAMP guide for computer systems. It is just more specific.

Q: Do many companies performance checks with quality control samples aside from system suitability testing (SST)?

Not in the pharmaceutical QC analysis. The reason is that SST is required by USP and the FDA wants to see it. So other QC checks that have to be done is additional work, not really required by USP or FDA. The concept of quality control checks is a better one and widely used in other industries, e.g., environmental testing or chemical testing.

Q: What do FDA inspectors expect from daily calibration of balances

Inspectors very much like to say a daily qualification of analytical balances with three reference weights. Such test including documentation takes about 5 minutes and inspectors get a better feeling.

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