Because of their potential for impacting product quality, laboratory instruments are key targets of FDA inspections. During an inspection, the FDA will expect to see definitive evidence that instrument qualification schedules effectively control your manufacturing and testing processes. Lack of (or insufficient) qualification procedures and/or documentation are in fact frequently cited deviations in FDA inspectional observations and warning letters. In order to ensure your organization is compliant with regulations, let’s explore the relevant details regarding analytical instrument qualification and documentation.

Types of Instruments

The term “instrument” in this blog refers to any apparatus, equipment, instrument or instrument system used for analyses. The USP General Chapter <1058> Analytical Instrument Qualification classifies instruments into three categories to manage risk in the instrument qualification process:

Group A: Standard laboratory apparatus with no measurement capability or usual requirement for calibration (e.g., evaporators, magnetic stirrers, vortex mixers, centrifuges, etc.). Proper function of instruments in this group can be determined through observation, and thus no formal qualification activities are needed for this group.

Group B: Instruments providing measured values as well as equipment controlling physical parameters (such as temperature, pressure, or flow) that need calibration. Examples of instruments in this group are balances, melting point apparatus, light microscopes, pH meters, variable pipets, refractometers, thermometers, titrators, and viscometers. Examples of equipment in this group are muffle furnaces, ovens, refrigerator-freezers, water baths, pumps, and dilutors. Often, Group B instruments will only require calibration, maintenance or performance checks to verify proper function. The extent of activities necessary may depend on the criticality of the instrument for ensuring product quality.

Group C: Computerized laboratory systems that typically consist of an analytical instrument that is controlled by a separate workstation running instrument control and data acquisition, and processing software. Group C instruments will require proper calibration protocols, often including software validation, to ensure their proper functioning.

Examples of instruments in this group include the following:

• atomic absorption spectrometers
• differential scanning calorimeters
• dissolution apparatus
• electron microscopes
• flame absorption spectrometers
• high-pressure liquid chromatographs
• mass spectrometers
• microplate readers
• thermal gravimetric analyzers
• X-ray fluorescence spectrometers
• X-ray powder diffractometers
• densitometers
• diode-array detectors
• elemental analyzers
• gas chromatographs
• IR spectrometers
• near-IR spectrometers
• Raman spectrometers
• UV/Vis spectrometers
• inductively coupled plasma-emission spectrometers

While categorizing laboratory instruments into three categories provide a useful starting point when discerning what kind of qualification protocol is necessary for an instrument, it should be noted that the same type of instrument can fit into one or more categories depending on its intended use.

In addition, due to the wide diversity of laboratory instruments in use, and the different ways these systems are used, a single prescriptive approach for instrument qualification would be neither practical nor cost-effective. In general, a risk-based approach to instrument qualification should be followed to determine the extent of qualification activities necessary for any instrument. Generally speaking, the more critical an instrument is to product quality, and the more complex the instrument, the more work will be required to ensure adequate qualification status.

Software Validation with Instrument Qualification

It is becoming more and more difficult to separate the hardware and software parts of many modern analytical instruments. The software part of the more complex analytical instruments can be divided into different groups:

Firmware: Many instruments contain integrated chips with low-level software (firmware) that is necessary for proper instrument functionality. In most cases, the firmware cannot be altered by the user and is therefore considered a component of the instrument itself. Thus, no qualification of the firmware is needed – when the instrument hardware is qualified at the user-site, the firmware is also essentially qualified. Group B instruments fall into this category. In this case, the firmware version should be recorded as part of Installation Qualification (see below) activities, and any firmware updates should be tracked through change control of the instrument.

Some instruments come with more sophisticated firmware that is capable of fixed calculations on the acquired data, or even firmware that enables users to define programs for the instrument’s operation. Any firmware calculations need to be verified by the user, and firmware programs need to be defined and verified by the user to demonstrate that they are fit for intended purpose. User-defined programs need to be documented in change control and access to them should ideally be restricted to authorized personnel.

Instrument Control, Data Acquisition, and Processing Software: More complex analytical instruments are typically controlled by a separate workstation computer running instrument control and data acquisition, and processing software. Since the software is needed for data acquisition and calculations, both the hardware and software are essential for obtaining accurate analytical results from the instrument.

The software in these more complex instruments can be classified into three different types:

• non-configurable software that can’t be modified to change the business process
• configurable software that includes tools from the vendor to modify the business process
• configurable software with customization options (i.e., custom software or macros to automate the business process)

In these cases, the software is needed to qualify the instrument and instrument operation is necessary when validating the software. As a result, the software validation and analytical instrument qualification (AIQ) can be integrated into a single activity to avoid duplication.

Qualification Process and Required Documentation

AIQ is not an isolated event, but instead consists of interconnected activities that occur over the lifetime of the instrument. The first step involves the creation of user requirements, which effectively specify the operational and functional requirements that the instrument is expected to fulfill. The user requirements must define every requirement relating to safety, identity, strength, purity, and quality of the product.

The next steps in qualifying an instrument and establishing fitness for purpose proceed as follows:

Design Qualification (DQ): The DQ seeks to demonstrate that the selected instrument has all the capabilities necessary to satisfy the requirements. As such, the DQ will document the requirements, along with all decisions made in selecting an instrument vendor. This information will help ensure that the instrument can be successfully implemented for the intended purpose. Verification that instrument specifications meet the desired requirements may be sufficient for commercial off the shelf (COTS) instruments. However, it may be wise for the user to verify that the supplier has adopted a robust quality system that serves to ensure the vendor specifications are reliable. If the use of the instrument changes, or if it undergoes a software upgrade, it is important for the user to review and update DQ documentation.

Installation Qualification (IQ): The IQ documents the activities necessary to establish that the instrument was received as designed and specified, is correctly installed in the right environment, and that this environment is suitable for the proper use of the instrument. Depending on the results of a risk assessment, IQ may apply to any new instrument, pre-owned instrument, onsite instrument that has not been previously qualified (or qualified to industry standards), or a qualified instrument that is being moved to another location.

Operational Qualification (OQ): The OQ documents the activities necessary to verify that the instrument functions according to its operational specifications in the user environment. OQ demonstrates fitness for selected use and should reflect the user requirements. OQ activities should simulate actual testing conditions, including worst-case scenarios, and be repeated enough times to assure reliable testing results.

Testing activities in the OQ phase should include the following parameters:

• Fixed Parameters – These tests measure the instrument’s non-changing parameters (e.g., length, height, weight, voltage inputs, acceptable pressures, loads). These parameters will not change over the life of the instrument and therefore do not need to be retested. If the user trusts the manufacturer supplied specifications for these parameters, these tests may be waived.
• Software Functions – When applicable, OQ testing should include critical elements of the configured software to show the instrument works as intended. Functions applicable to data acquisition, analysis, security and reporting, along with access control and audit trails, should be tested under actual conditions of use.
• Secure data storage, backup, and archiving – When applicable, secure data storage, backup and archiving should be tested at the user’s site.
• Instrument Function Tests – Instrument functions that are required by the user should be tested to confirm that the instrument is operating as the manufacturer intended. Supplier information can be used to identify specifications for this testing, as well as to design tests that verify that the instrument meet’s specifications in the user environment.
• Software configuration and/or customization – Configuration or customization of instrument software should be documented and occur before any OC testing.

Performance Qualification (PQ): Also sometimes called user acceptance testing (UAT), PQ testing intends to demonstrate that an instrument consistently performs according to specifications appropriate for its intended use. PQ should be performed under conditions simulating routine sample analysis. As consistency is important in PQ, the test frequency is usually much higher than in OQ. Testing can be done each time the instrument is used, or scheduled at regular intervals.

Preventative Maintenance, Periodic Reviews and Change Control

Preventative maintenance (e.g., calibration), periodic reviews, repairs and other changes should be documented as part of instrument qualification requirements. When an instrument malfunctions, the cause should be investigated and documented. Once maintenance activities, changes, upgrades, moves and reinstallation at another location, or a repair is complete, relevant IQ, OQ and PQ tests should be run to verify the instrument is operating satisfactorily.

Critical instruments should undergo periodic review to confirm that the system is still under effective control. Areas for review may include: qualification/validation status, change control records, backup and recovery systems for records, correctness and completeness of records produced by the instrument, change control records, test result review and signoff, user procedures.

A change control process should be established in order to guide the assessment, execution, documentation and approval of any changes to laboratory instruments, including firmware and software. All details of the change should be documented, and users should assess the effects of the changes to determine if requalification (IQ, OQ or PQ) activities are necessary. It is important to note that, depending on the nature of a change, qualification tests may need to be revised in order to effectively evaluate the instrument’s qualification status after the change.

Conclusion

Analytical instruments can provide a high level of confidence in the quality of finished product through scientific data if they are qualified properly. Instrument qualification is an important part of compliance for laboratories in regulated industries and is important to ensure product quality and safety in any industry. Failure to qualify instruments properly can lead to serious consequences for an organization as a result of compliance violations and poor product quality.

Instrument qualification plans should be documented in the Validation Master Plan (VMP) and implemented by documenting user requirements and following the DQ/IQ/OQ/PQ protocols outlined in this blog. In order to demonstrate a commitment to manufacturing quality products, organizations should work to:

• develop a VMP that encompasses the entire validation
• implement well thought out AIQ qualification programs.
• implement a regular requalification plan for critical instruments (annually at minimum).
• maintain current SOP documentation.
• take appropriate steps to ensure data integrity and data security

While a commitment to quality requires much effort and focus, industry leading organizations understand that good quality practices and culture lead to a more efficient work environment, improved employee satisfaction, and ultimately increased profitability.

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