Equipment qualification for demonstrating the fitness for purpose of analytical instrumentation: C. Burgess,* Dianna G. Jones and R. D. McDowall B.IM. Limited, Rose Cottage, Walker Hall, Winston, Darlington, County Durham, OK DLI2 3PN Received 19th June 1998, Accepted 16th July 1998 Equipment qualification is the way to ensure that analytical equipment is fit for purpose. Qualification consists of four basic elements. Design qualification or DQ (Specification of what exactly the analytical seientist requires the {equipment to do). Installation qualification or IQ (Does the instrument Work to the manufacturer's spec Operational qualification or OQ (Does the instrument work the way’ the analytial scientist wants i t0?) and performance qualification or PQ (Does and approach di Qualification of analytical instruments cannot be achieved through method validation. Equipment qualification provides the foundation to develop, validate and run analytical methods within the operating range measured. If method is developed using parameters out of this range, then the analytical instrument needs to be re-qualitied before method validation ‘can proceed. Seven case studies of qualifying equipment, such as high- performance liquid: chromatographs, environmental storage equipment, centrifuges and pH meters illustrate the importance of a structured and logical approach to the subject. ‘The Key clement that is missing in the majority of laboratories’ approach to equipment qualification is that design Qualification is often lacking. Hence, unsuitable and in- appropriate equipment is purchased which can be difficult t0 ‘qualify for its intended purpose Introduction Analytical sciemtists place great faith inthe readings and outputs from their instruments. When unexpected or out-of-specitica- tion results occur, the intial suspicion often falls on the sample, the preparation technique or the analytical standard employed, Rarely does the analytical scientist immediately question the equipment. Indeed, the whole underpinning of method valida: tion assumes that the analytical equipment which is used 4 acquire the experimental data is operating correctly and reliably. We will return to What is meant by correctly and reliably Title later Some industries. which operate in a highly regulated environment, such as the pharmaceutical industry, have placed great emphasis on method validation in, for example, HPLC." However, uni recently, there has been litle direct requirement for assuring that the’ analytical instruments are working Property. The American Food and Drug Administration specifically requites that ‘Laboratory controls shall inelude.....the calibration of instruments, apparatus, gauges and recording devices at suitable intervals in accordance with an established Written program containing specific directions, schedules, 4 The opinions eyes in dhe fllowing area ar eel thse of the curs ind Jo noe necessarily repescat the views of iter The Royal Shetty of Chemis ote Editor of The Anlst Continue to operate within the parameters monitored?). The background cussed inthis paper has been developed primarily within the pharmaceutical industry. limits for accursey and precision and provisions for remedial action in the event accuraey andlor precision limits are not met. Instruments. apparatus, gauges and recording devices not ‘meeting established specifications shall not be used.” ‘The major regulatory guidlines for Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) are similarly vague. “Fitness for purpose” is the phrase that is ‘commonly used, but what docs this mean in practice? Only the Pharmacopoeias*® and the Australian Regulatory Authoriy® have been sufficiently worried by instrumental factors t0 give Written requirements for instrument performance. Whilst these guidelines are not consistent at least they are attempting 10 ensure consistent calibration practices between laboratories In contrast, the ISO Guide 25 approach’ heavily focuses on good analytical practices and adequate calibration of instra- lly oF imernationally traceable standards However, there has been a resurgence of interest in the underlying dats quality by regulatory authorities, particularly the FDA (Food and Drug Administration) in the USA. following a major legal ruling*in 1993, This case has chan the regulatory focus and put the laboratory fir spotlight in terms of the assurance of the quality of the data it produces. The details of the Barr ease need not concer us, although it i useful to review the key features because of the impact they had on FDA thinking in particular and regulatory Perspectives in general ‘The Barr ruli is ‘The most important point about the Bare ruling is that it was the Fist time that the GMP regulations and their interpretation by the FDA had been subjected 10a comprehensive judicial review. ‘The written decision covered 79 pages. As Judge Wolin decided in favour of the FDA, this greatly strengthened their enforce- ‘ment activites as well as other regulatory aspects, The FDA investigated Barr Laboratories over a peried of 4 years, having noted deficiencies in their manufacturing. process validation. FDA had issued Warning Letters to the company which were effectively ignored. However, as a result ofthis investigation it emerged that effectively the company was “testing into ‘compliance’, Pharmaceutical companies are required to register the acceptable limits for release of product into the market Analyst 1998123, 1879-1886 1879and in others out-of-specification results were rejected or ignored when batch release was undertaken, ‘One quotation from the FDA document will serve to illustrate the agency's concern; ‘During the enforcement litigation, Barr prepared reports on investigations into out-of specification resulls on certain batches of some of its products. These investigations reflect Barr's persistent efforts to avoid attribut- ing out-of-specification results to process-related. problems rather than identifying the causes of the out-of-specification results and correcting them 10 prevent their recurrence. Repeated similar out-of-specitication results implicating the manufacturing process were attributed alternatively 10 operator certor, equipment error oF laboratory error.” (One ef the consequences of the case has been the thrusting of| basic laboratory procedures and practices into the spotlight. tis fnow an FDA requirement to investigate formally all outof- specification results. Therefore, validation of methods and, for the first ime, the qualification of analytical instrumentation. are ‘being heavily serutinised. ‘Such was the concern that FDA Guidance on QC Laboratory Certification” was developed by former FDA Mid-Atlantic Region NDAANDA Technical Operations Group Manager Henry Avallone to help explain the concept of laboratory certification to field office personnel. He identified eight main areas to be addressed for laboratory certification: management Systems; operating procedures: personnel training; data_ac- ‘countabilty; method validation: equipment; [cilites; cemtifica- tion documentation. This list will be very Familiar to those operating in an ISO, Guide 25 (NAMAS or equivalent national agency) accredited laboratory. Indeed, the majority ofthese items were not new 10 the pharmaccutical industry. What was new was an explicit statement of requirements for the qualification of laboratory equipment, “The qualification of laboratory equipment and the jaitenance of such equipment, along with the adequacy of standards, reagents and test solutions are of conver in the certification ofa laboratory. For the microbiological laboratory ‘organism viability, media growth promotion, incubators, auto- claves, hoods and automated equipment used for organism identification all require qualification and calibration. There- fore, it would seem that in order to certify a laboratory, ‘equipment should be listed, along with documentation that itis Adequate and operating effectively for its intended purpose. Ibis also. good laboratory practice to have a quality assurance program that will assure that reference standards, buffer Solutions, titrating solutions, reagents and other apparatus are adequate and maintained properly. Fr some equipment, such as HPLCS and test systems that they may be a part of, a holistic approach rather than a qualification of each component part such as 8 pump, may be used. This method! has been found ‘acceptable as written by Furman et al’! Modular and holistic qualification Furman er al, discussing the validation of computerised liquid chromatographic systems, present the concept of modular and holistic qualification. Modular validation isthe qualification of the individual components of a system, such as the pump, autosampler, column heater and detector of an HPLC, The tuthors make the point that whilst ‘calibration of each modiule ‘may be useful for troubleshooting purposes. such tests alone feannot guarantee the accuracy and precision of analytical results” ‘Therefore the authors introduced the concept of holistic validation, where the whole chromatographic system was also ‘ualified to evaluate the performance of the system. 1880 Analyst, 1998, 123, 1879-1886 ‘The reader may question why such an approach is needed. ‘One pragmatic reason is that in our experience it is necessary! We cite an HPLC system that was qualified by us and the jual modules were just within acceptable Timits. How- ‘ever, when a holistic test forthe whole system was carried out, the system failed to meet the ‘suitability for use” criteria. "The concept of holistic qualification is important as some laboratories operate with a policy of modular equipment purchase. Here they select components with the best or ‘optimum performance from any manufacturer. Furthermore, to ensure optimum throughput, some of these latoratories may swap components when they malfunction, Thus, over time, the composition of system may change. Therefore, 10 assure themselves and any regulatory bodies thatthe system continues to function corectly, holistic qualification i vital Some laboratory equipment requires maintenance and pre- ventative maintenance (PM) programs should include such ‘equipment. For example, HPLC units, spectrometers and autoclaves all require routine preventative maintenance. Reg- lulations require that equipment include maintenance logs or documentation. Therefore, laboratory cerification should pro- vide for a review of the preventative maintenance program. ‘Management usually only sees the topmost layer of these processes and is probably unaware of the ‘iceberg’ that lunderlies them, This aspect is shown pictorially in Fig. 1, wheteby only the tip ofthe iceberg is generally visible ‘What the Barr Ruling has done isto shift regulatory attention ‘downvvards into the data level which hitherto it had not overly ‘concerned itself with Approaches to integrity of analytical results “The “bottom up" approach is the one usually favoured by the analytical specialists. Like “Lego'. the quality ofthe end result is built in from the foundations up. In testing terms this is illustrated in the diagram below (Fig. 2). These “Lego” bricks ‘re equivalent to the individual modules in any measurement system, Each brick is qualified as suitable for use before the ‘next layer is built, In this way, integrity is assured all the way 10 the topmost layer. If firm foundations are not built, the information generated will ot stand scrutiny. By following this approach quality is bull in from the lowest level. “The role of the instrument in providing the integrity of data is| fundamental to the end result, If you cannot place your faith in the reliability of the basic analytical signal within pre- cemnatogaphy, 1 an n ‘ dissin esting. efacve index, 831 > spe ropocometry ad ight searing Bruis Pharmescoporia 1983, Nppenic U:Inrared spctopot rmaty, Ulmlet and Visible Spectophotometry (Pharm. Bur Vo Absorpion Spectophaconett). HM Stationery Ofice, ondoa. 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