A Quick Guide to the Qualification of HPLC Devices

The pharmaceutical industry is heavily reliant on HPLC techniques, both for quality control purposes as for research, and it is not hard to see why. It is one of the most versatile techniques out there, allowing for separation of complex mixtures of compounds and simultaneous qualitative and quantitative assessment. However, because of this strong reliance on HPLC equipment, good qualification and maintenance practices are critical. In this post, we’ll explore several important points to keep in mind during the entire life cycle of your HPLC equipment.

1. The initial qualification

Congratulations, you are the proud owner of a brand new HPLC unit! However, before you get to play with your latest toy, there are a few steps to take. Usually, the manufacturer will perform a series of controls on-site before signing off on the delivery. Then your qualification process can begin. Especially in GMP controlled environments, this process includes a lot of documentation and paperwork.

HPLC devices are complex machines consisting of many separate modules. A typical setup consists of several pumps, an injection system, a mobile phase degasser, lots and lots of tubing, a column housing, an autosampler system and one or several detection systems. A series of checks must be performed to ensure each component is functioning as required. Examples include measuring if the flow corresponds with the setpoint using an external calibrated flow meter, checking temperatures of any heating and/or cooling unit, verifying the proper mixing of mobile phase components and checking the response of detectors. Results of all of these checks need to be documented according to ALCOA guidelines (you can read more about those here) and bundled in an initial qualification report file, along with all the information provided by the manufacturer.

Besides all of the per component checks, it is good practice to also test the equipment the way it will be used: as a whole. This method is often referred to as holistic testing. The most practical way to do this is to perform specific assays using reference materials and compare the resulting chromatogram to what is expected. Are all peaks separated well and do they have the right shape? Do retention times correspond with what you expect to find?

If the device passes all tests and the documentation is approved, it can be taken into routine use. All of the data and documentation generated during the initial qualification process, including the testing performed by the manufacturer, must be archived carefully and in such a way that it is easily accessible. It is common for this kind of data to be requested during GMP audits, and it makes a better impression if the full data package can be produced swiftly.

2. Maintenance and periodic requalification

Now that you have ensured your device works as it should, it is important to ensure that remains that way. Key to this is, of course, periodic maintenance, usually by the manufacturer and yearly or after a set number of runtime hours. Every service intervention should be carefully documented of course. In addition to this, it is always wise to have a stock of spare parts close at hand. In many cases, manufacturers of HPLC equipment have lists available of the estimated lifespan of individual components. Study this list carefully, identify the components that will need replacing most frequently and make sure you have these available at all times. This small investment could save you a lot of time and money in the long term.

Although important, preventive maintenance is not enough to guarantee continuous system performance. Equally important is to verify all is working well regularly. A yearly requalification is recommended consisting of a list of checks similar to the ones performed during the initial qualification, but usually not quite as elaborate. A more thorough requalification can be scheduled on a longer timeframe, for instance, 3 years. Requalification may also be necessary after repairs, although a bit of common sense should be applied here. For instance, if a technician only replaced the lamp of a UV-VIS detector there is, of course, no need to check the pump linearity or column oven temperature stability. After a major repair or system overhaul, however, a more elaborate requalification may be required. To guarantee uniformity in testing and GMP compliance, these procedures should be registered formally in Standard Operating Procedures (SOPs) with clearly defined timeframes and strict criteria for testing.

An annual requalification usually consists of several component checks, sometimes followed by a holistic test. Annual requalification typically focusses on the parts of the device that have the most direct influence on the proper application of test methods: the pump and the detection system. The right flow and the correct mixing of mobile phase components are vital for correct separation of peaks, and the detection system is critical for the proper recording of data. The longer-term requalification procedure should take a broader approach more akin to the initial procedure.

Additional to the entire qualification process, it is important to perform adequate system suitability tests (SST’s) before each run with well-defined acceptance criteria. Typical SST parameters are resolution, repeatability, column efficiency and tailing factor (also referred to as symmetry factor). These tests are the final check of your equipment right before, during and after the generation of GMP critical data. The guidelines for SST’s are defined by the International Conference on Harmonization (ICH) and can be found in the Pharmacopeias. Compliance to these guidelines is critical in GMP controlled environments.

3. Things to keep in mind

When designing a qualification strategy for your lab’s HPLC devices there are a few important points to keep in mind.

  • Be thorough. For example, when testing the performance of a pump system, don’t just check flow accuracy, also check for linearity and flow stability. The same goes for the qualification of a detection system, don’t just test if you get an absorbance peak at the right wavelength, your qualification data should be able to prove that the detector provides a linear response and does so in a reproducible way.

  • Be complete and thorough in the documentation. Quite often, the decision to release batches of drug products to market rides at least in part on the results of HPLC analysis, so it is vital to prove the proper functioning and qualification status of your equipment at all times.

  • Create uniformity in the documentation. Especially if your lab operates a large number of HPLC devices, make sure the documentation of qualification events is uniform and clear. This will make it a lot easier to find data when necessary and will make documenting of these events a much more streamlined experience.

  • Keep a clear overview. Make sure you know at all times which devices are due for requalification at which times and plan accordingly to minimize downtime of equipment. Make sure the analysts performing the qualification procedures are given enough time to work with the required precision, there is no need to rush these things.

  • Create a document where every problem that you ever encountered with a specific type of device is listed along with how the problem was solved. Over the years of service, this will become an invaluable tool for troubleshooting, since you will be able to refer back to experience, often saving you a lot of investigation time.

If you have any other questions or you are looking for support in your qualification efforts, we are here to help.

Blog by Jonathan Caramin