Do you know your calibration from your validation and your verification from your qualification? Paul Smith gives us a handy guide to the often daunting subject of laboratory compliance

Do you know your calibration from your validation and your verification from your qualification? Paul Smith gives us a handy guide to the often daunting subject of laboratory compliance

WHAT is laboratory compliance? It is a general term used by many people, but which means different things to different people. There is no definitive answer or even one in Wikipedia the online encyclopaedia! For me, it is the name applied to the procedures, policy and general approach used in a laboratory to ensure that the analytical results generated are meaningful, valid and suitable for the decisions which will be made from the data. This fundamental statement applies to all laboratories and can be represented by the quality pyramid shown in Figure 1. What differs about laboratory compliance between organisations and industries is:-

• The approach they use to demonstrate that the data is valid
• The level of rigour they apply to the documentation
• The level of compliance monitoring used
• Where most emphasis is placed in the pyramid in Figure 1.

Even the laboratory compliance terminology used can also differ in meaning – another potential source of confusion. Many of the terms encountered are used in an interchangeable manner. For example, calibration, qualification, verification or validation may mean something very similar or something very different – at present it is necessary to clarify the exact meaning of the phrase by asking the person who uses it for examples. The clarification provides a context which enables us to interpret the meaning of the phrase and compare this meaning with our own understanding. This level of detailed understanding is critical when comparing qualification services between organisations.

One of the key secrets to robust compliance which supports value driven analysis and a low risk audit defence strategy lies in understanding the inter-relationship between the laboratory compliance levels of the pyramid in Figure 1. The levels must not be considered in isolation from each other and all of the levels are fundamental parts of the laboratory quality management system (QMS). However, any level will have a different general interpretation in a given industry. Additionally, independent of industries the approach used by suppliers to qualify their instruments varies considerably (more later). The impact of this variation means that presenting a harmonised instrument qualification approach, as part of a robust regulatory audit defence is unexpectedly difficult - because of the different and fragmented qualification approach by suppliers. The remainder of this article will focus on analytical instrument qualification (AIQ), acknowledging that this should not be considered in isolation from the other levels shown in Figure 1.

A detailed history of trends in AIQ has been published previously1. The purpose of this article is to provide a framework to help people understand some of the implications of this history against laboratory compliance needs, explain the origin of variation in supplier qualification and provide an update on more recent information / guidance. Fundamentally, analytical instruments must be qualified (to show they are working properly) before analytical methods are developed and validated using the instrument. If the instrument is not working properly, the method development and validation are invalid.

QAI was first implemented in the pharmaceutical industry, although the general principles of needing a framework to document that an instrument is suitable for its intended use are applicable to all laboratories and all industries. Would a laboratory knowingly buy an expensive instrument which was not appropriate, use it in a way which was not valid and knowingly make decisions from data which simply not suitable? The answer, of course, is no. However, by not qualifying the equipment, this is exactly the risk which laboratories operate.

The initial qualification has to include consideration of what the instrument will be required to do (the URS - user requirement specification). A simpler way of understanding this is to consider things such as:-

• What samples will be tested
• How will the samples be tested (what methods and operating ranges/accessories will be needed)
• What results the instrument be used to generate
• What level of uncertainty is needed (especially important for trace analysis)
• What level of confidence is needed in the results (in relation to the process capability2)

The original FDA validation guidelines were developed for pharmaceutical manufacturing process validation3. When analytical instrument qualification was in its infancy, the process of interpreting these guide lines and then re-applying them to analytical instrumentation resulted in significant process validation bias and variation in interpretation. Hence, the approaches taken by organisations to AIQ, from multi-vendor qualification suppliers (independent of manufacturer), suppliers of analytical instruments through to industry and compliance consultants varies significantly. Typically, variation is modest for the IQ, but can be significant for the OQ and PQ, even down to the scope of what these sections should contain.

In addition to this historical fragmentation - in absence of a more authoritative guide from regulators, the pharmaceutical industry in particular turned to good automated manufacturing practice (GAMP) for a validation framework, which introduced a software-driven approach. Earlier this year, GAMP 5 - A Risk Based Approach to Compliant GxP Computerised System - was published4.

However, in August 2008, the United States Pharmacopeia (USP) monograph on

Both GAMP 5 and AIQ <1058> employ risk based thinking and increasingly, the general principles of risks based thinking are also being applied by regulatory auditors. Therefore, there is an increasing expectation that laboratories will use risk based thinking. One way to overcome IQ/OQ/PQ variation is to move to a support model for the laboratory where all of the equipment maintenance and qualification needs are supported by the same organisation, harmonising the qualification rationale.

In principle, these differences could be resolved by defining and agreeing what the DQ, IQ, OQ and PQ should contain, as well as the other differences between AIQ <1058> and GAMP 5. One

• Definition of roles and responsibilities
• Outline of the qualification process
• Implementation of risk based thinking
• Potential simplification of the Qualification process
• Maximise use of supplier derived information.

Because they have been developed in isolation, they approach Qualification from different perspectives. GAMP 5 is a rigorous project management approach to Qualification derived from a software development focussed perspective which can be applied to the most complex bespoke software and/or instrument. The Gamp 5 book is 352 pages of well developed and well written text and is supported by a number of good practice guides (GPG) developed by industry gamp special interest groups (SIG). If a laboratory was designing a new laboratory information management system (LIMS) or some other bespoke software package, Gamp 5 would be excellent.

For most laboratories however, the process may simply be too rigorous for

A metrology based approach to qualification naturally overcomes these difficulties – as calibration of the tools automatically corrects for measurement bias and the uncertainty of measurement is designed in and reported with the results. This leads to greater accuracy of results and a higher level of confidence that the instrument is working correctly.

Ideally, the full operating range of the instrument must be qualified as extrapolation of results is not good practice and results in greater risks. Additionally, as well as spanning the range of operation, instead of simply measuring the actual minimum and maximum setting, it is desirable to include settings which are close/at the most commonly used values.

If analytical instrument qualification was being introduced now for the first time, many of the causes of variation which are historically related would probably not exist. However, we do not have that luxury, therefore, we have to manage the variation and the differences and decide how laboratories achieve their compliance. Out of the two main qualification approaches introduced this year4, 5 the impact of these on regulatory audits is currently unknown and will only become better understood following a number of FDA audits, when interpretation of these two documents is understood. Both Gamp 5 and AIQ <1058> have advantages. Gamp comes into it's own for large bespoke software systems (such as LIMS or custom robotic automation). However, for most laboratory equipment, it is may be too complex to be practical (with the exception of laboratories which are already aligned).

AIQ <1058> is much simpler than GAMP – but only provides a general framework for qualification, it does not provide the detail. In doing so, it simplifies the process, removes the mystique and therefore makes it easy for all laboratories to understand and follow.

The variation in qualification approaches is a cause of frustration because it makes the strategic job of audit preparation difficult. There is no strong driving force within the service industry to harmonise approaches. Therefore, if a laboratory wants to implement a harmonised consistent approach to analytical instrument qualification, it will either have to qualify all the equipment itself or move to an outsourced multi-vendor qualification model.

When considering the qualification approach a supplier is using, it is essential to understand the detail of the approach, especially when prices are being compared. Out of the qualification approaches used, a metrology driven qualification approach which includes both qualification of the operating range of the instrument and settings that are commonly used in the applications (methods) presents the ideal option in the opinion of the author.