Qualifying laboratory instruments

 

In recent years, the documented qualification of analytical instruments has become increasingly important. Although equipment tests were carried out previously, a comprehensive qualification system has been in place only recently. The international requirements and guidelines for the qualification of equipment, premises and facilities for production (see chapter 3 Premises, chapter 4 Facilities and Equipment and chapter 6 Qualification) have to be adopted to the analytical instruments.

In a compehensive quality assurance system (TQM) the basic requirements for correct analytical results can be found not only in validated analytical procedures (see chapter 14.F Validation of analytical methods), but also very significantly in qualified and regularly calibrated analytical instruments (see chapter 14.E Calibration in the lab).

The qualification of equipment is the evidence that the relevant analysis equipment is suitable for the intended use. This evidence must be generated in writing and shall be subdivided into 4 logical sections:

DQ Design qualification equipment evaluation and selection
IQ Installation qualification equipment installation
OQ Operational qualification equipment function testing
PQ Performance qualification suitability for use testing

In recent times, computer validation (see chapter 9 Computer Validation) has added a fifth dimension to the above, with most analytical instruments operated and controlled via a PC, which also carries out the calculations. For each section, the first requirement is to compile a qualification protocol. The tasks must then be carried out following this plan, the results evaluated and, finally, recorded in the qualification report. This planning - execution - evaluation - reporting procedure is a general principle in the GMP-regulated environment, touching on all areas and, for example, on the processing of OOS results in particular (see chapter 14.H Out-of-specification results).

Q7a - Qualification: Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

11 Qualification protocols and reports

The qualification protocol must be compiled before the qualification begins. The plans must be tailored to each stage and play a significant part in conducting a flawless qualification of the apparatus. Plans and reports can also be compiled for several stages together. They should be brief and succinct and the main elements, particularly the activities to be carried out, should be described in such a way that they are easy to interpret.

11.1 Design qualification (DQ)

The design qualification documents the alternative decisions and methods which led to the analytical apparatus requirements, making it possible to guarantee that the adequate level of quality during selection was taken into consideration.

During this stage, the DQ plan describes the offsetting of the user requirements against the vendor specifications (proposals for the conversion of the user requirements by the equipment manufacturer/supplier). This stage involves comparing pieces of apparatus from various manufacturers in terms of both performance and price. The performance criteria does not simply include the design and the functioning of the apparatus.

The following items are also very important:

• Selecting the manufacturer (auditing possible, QA available, SOPs available, Change Control implemented, documented training of service technicians, spare parts stores, availability of after-sales service, after-sales service costs, adoption of several stages of the qualification process, service contract)
• Model selected (space required, extension possibilities, user friendliness)
• Compatibility with company's IT environment (hardware, software)

Many companies have already started to carry out risk analyses as a component of the qualification process for this phase. Using the FMEA (Failure Mode and Effects Analysis) methods (Sahni, 1993) taken from the manufacturing methods, the implementation of a risk evaluation for each important function of the equipment is being attempted. This involves making distinctions according to the frequency of the faults, the severity of the fault and the likelihood of recognising the fault.These three evaluation items are then weighed up individually within 5 classifications and the number of points obtained equal the risk factor when multiplied together (see figure 11).

For a factor of up to 125, the function of the appliance is considered in the qualification, if the factor is larger than 25 to 30. C. Wangnick has made this clearer in his example of the qualification of an HPLC equipment (Wangnick, 1997). This example involved evaluating the modules pumps, auto samplers, detectors and column ovens according to various functions (see figure 12).

These risk factors can also be applied to select the test items for calibration derived from the critical parameters in the qualification (see chapter 12.1 Test intervals, test points, test instructions). The results must be recorded in the DQ report. The report is filed within the qualification documentation.

11.2 Installation qualification (IQ)

The installation qualification is used to provide documented evidence that the analytical equipment was supplied in accordance with the order and the specifications. This also includes the assembly and the connection of the apparatus through to the buyer's final acceptance.

The IQ protocol stipulates that the delivery must be inspected to check that it is complete and accurate in accordance with the delivery note. This inspection shall include:

• List the apparatus with all its components (in tabular form) (model description, serial number of the component and (internal) equipment or inventory number)
• Completeness of the technical documentation
• Availability of the operating instructions (in the correct language)
• Inspection of all components, installation and connection (including PC)

Finally, an instrument logbook must also be kept and a calibration SOP compiled (risk evaluation).

The results of the inspection shall be recorded in the IQ report. The report is included with the qualification documentation.

11.3 Operational qualification (OQ)

The operational qualification is used to document that the individual components of the analytical instrument are functioning properly ("switch is ON, the light is on").

The OQ protocol shall specify that:

• a preliminary training was given by the supplier
• general functioning tests will be carried out
• the technical documentation will be inspected to make sure that it contains safety instructions, hints for trouble shooting in the event of malfunction, maintenance instructions, product care and cleaning instructions, a spare parts list (order number, telephone number, place to order from and after-sales service).

The OQ report is used to record the above mentioned items in writing and is filed within the qualification documentation.

11.4 Performance qualification (PQ)

The performance qualification is used to provide documentary evidence that the analytical instrument functions perfectly in accordance with the OQ, and also functions together with all the instrument components. This includes the PC that is used to operate and control the apparatus and evaluate and administer the data.

The OQ plan shall specify that:

• a function inspection in conjunction with all the components according to the list of critical parameters (risk analysis) must be carried out.
• supplementary operating instructions must be compiled
• the apparatus shall be released for use

The PQ report is used to record the above mentioned items in writing and is filed within the qualification documentation.

If the computer validation (see chapter 9 Computer Validation) is not conducted separately but is considered as part of the PQ - for the purpose of the functioning of the entire system and control and evaluation units - this must be recorded in the PQ protocol. This will involve checking parameters such as those for the hardware configuration, the general software operation, wrong entries, system security and stability (Y2K problems) and also security of access (password protection) (see chapter 9 Computer Validation).

12 System suitability test (SST)

The system suitability test is the logical continuation of instrument qualification through to guaranteeing the availability of the instrument in daily use. The USP stipulates that each analysis series must be inspected to check if the system is suitable for the intended use. A distinction is made between the apparatus-specific SST and the method-specific SST.

When conducting the apparatus-specific SST e.g., a triple determination is conducted for determining the melting range on a daily basis using a calibration substance (e.g. vanillin). If the requirements have been fulfilled, this guarantees that the apparatus is ready for daily use.

The method-specific SST is used to test the suitability of the method-apparatus combination for the method in question (e.g. determination of content of active pharmaceutical ingredient X in product Y using HPLC). The parameters and requirements to be tested are derived from the instrument qualification results (above all from the PQ) and from the results of the method validation. In this context, it must also be stipulated that the SST must be carried out for every test series (and not just on a daily basis), the requirements (e.g. requirements relating to precision, resolution, limit of quantitation, peak symmetry) must be defined and the preparation of the solutions to be used as well as the test procedure must all be described separately.

In practice, it is known that for many older products in particular there are no testing procedures which give clear and comprehensive details on how to conduct the SST. It is advisable to set out the general procedure in an SOP in such cases. The reference to pharmacopoeia alone is not sufficiently clear since the USP stipulates in chapter <621> Chromatography for the SST in assay determination:

Multiple injections of standards are necessary in order to check the precision. If nothing else is specified in the testing procedure, then

• the relative standard deviation (RSD) is determined using 5 injections if the requirement is £ 2.0%
• the relative standard deviation (RSD) is determined using 6 injections if the requirement is > 2.0%

It must then be specified whether in general 5 injections (with RSD £ 2.0%) or 6 injections (with RSD £ 3.0% or £ 2.5%) should be used.

It is therefore recommended to define the SST in the testing procedure (see chapter 15.C.4 Testing procedures and test protocol).

After the qualification has been completed successfully, the instrument is released for use. Periodical tests (see chapter 14.E Calibration in the lab) guarantee that the qualified status is maintained. If changes are made to the instrument a requalification must be carried out, the contents and scope of which are derived from the OQ and PQ experiences. This must be specified in writing in the associated plans and reports and filed in the qualification documentation (see chapter 19.C Change control).