Laboratory Integrity
New ISO Standard Answers Growing Demand for Data Integrity in the Laboratory
Technologies often develop more quickly than regulatory agencies can respond. This is especially true in drug discovery and development due to the rapid pace of new technological breakthroughs. Liquid delivery quality assurance is no different. In the face of advancing capabilities of liquid handling instrumentation, increasingly complex assays and an industry-wide push for greater efficiency, a growing need for enhanced liquid delivery quality assurance has emerged, as has a solution.
The photometric method is the latest addition to the laboratory quality assurance tool kit, measuring light absorption to verify the performance of liquid handling instrumentation with a high degree of accuracy and precision, and is especially effective at low volumes. Although the trend toward low-volume assays is not new, until recently, there was no official guideline or recommendation for photometric calibration of liquid handlers. The International Organization for Standardization changes this with the approval and publication of a new standard, ISO 8655-7, formally making this advanced and convenient methodology an internationally accepted standard method.
Photometry and ISO 8655-7
ISO 8655-7 asserts that the photometric method "may be the method of choice" in assuring the performance of piston-operated volumetric apparatuses, which include manual and automated liquid handling devices. Previously, gravimetry was the only ISO-approved method for liquid delivery calibration. However, ISO acknowledged that this method, which weighs liquid quantities on balances, has limitations at low-volumes. Gravimetry also has limited applicability to multi-channel device performance verification, providing only an aggregate assessment of all channels as opposed to each individual channel. The gravimetric method further impedes testing by end-users because it requires a controlled environment to function properly.
ISO Technical Committee 48 recognized that users in pharmaceutical laboratories from RandD through manufacturing were in need of a new methodology to minimize uncertainty in liquid delivery verification, particularly at low-volumes. For this reason, the organization evaluated and consequently approved photometry for assessment of equipment performance. Relying on known light absorption properties at specific wavelengths, photometric methods can provide stronger assurance of data integrity, quickly and conveniently.
A highly accurate and precise application of photometry with a dual-dye approach to calibration is described in Annex A of the ISO 8655-7 standard. Called ratiometric photometry, this technique employs two highly characterized solutions to combat accuracy problems typically associated with low-volume measurement, yielding results with uncertainty less than one percent for volumes as low as 0.1�L.
New Demands
ISO's approval of the photometric method for calibration answers the demands that many laboratories are currently facing. A mounting focus on quality is one such demand. Although quality assurance has long been a critical component of downstream pharmaceutical processes such as manufacturing and packaging, upstream functions such as RandD have not faced such intense scrutiny. Recently, however, driven by quality demands, process controls and advancing FDA guidelines, laboratories have been tightening quality control programs earlier in the development cycle.
This is compounded by the increasing concern over rapidly increasing drug costs imparted on both consumers and pharmaceutical companies, with the average drug costing $800 million and needing seven years to reach the market. Pharmaceutical companies are under pressure to bring products to market more quickly and cost-effectively. This is especially true given that large investments in laboratory automation have failed to result in productivity gains. Laboratories are therefore seeking new methods to streamline their drug development processes from start to finish, including ensuring the performance of critical systems such as liquid delivery.
The Food and Drug Administration's (FDA) launch of its PAT (Process Analytical Technology) initiative is evidence of the trend toward process-wide quality. This program recommends that pharmaceutical manufacturers have a framework in place to consistently monitor quality and performance throughout the entire drug development process. Assessing accuracy and precision in real-time is consistent with the philosophy underlying the PAT initiative. The heightened focus on productivity makes accurate and precise volumetric measurement more crucial than ever.
This is especially true as growing reagent costs and scarcity drive laboratories to work with smaller liquid volumes. Drug companies are seeking new and superior methods to validate the performance of their liquid handling instrumentation to avoid wasting high-value liquids as well as to maximize investment in automated equipment by enhancing its productivity.
The cost of reagents is not the only price that drug companies pay for malfunctioning liquid handling instrumentation. Dispensing reagents in volumes inaccurate by even miniscule amounts, especially in complex serial dilutions, can alter concentration and prevent the identification of a reaction between compounds, the foundation for a new drug. These "false negatives" may cause a laboratory to miss the next breakthrough drug, an occurrence whose dollar value is almost immeasurable.
While American pharmaceutical laboratories have traditionally turned first to the FDA for guidance, American regulations are evolving towards greater harmonization with their international counterparts.
The cost of "false positive" results must also be considered. False reactions can lead companies to sink time and resources into pursuing dead end projects. Many drug target "hits" are pursued through initial discovery stages to be proven ineffective in later stages. Accurate liquid delivery quality assurance methods can strengthen the confidence that drug companies have in the results of their critical research, testing and development assays, avoiding waste and inefficiency.
The scarcity of laboratory resources is another trend driving the need for enhanced liquid delivery quality assurance. Laboratory technicians facing growing workloads due to a shortage of trained personnel not only need assays and experiments to be correct on the first run to avoid wasting time and resources, but also need a convenient method to ensure this. Photometric calibration gives technicians an easily implemented and user-intuitive tool for prompt performance verification.
The Role of ISO Regulations
In the constantly evolving pharmaceutical industry with new challenges and solutions emerging every day, it is often difficult for laboratories to know which technologies are passing, risky fads and which solid, reputable solutions are. This is the benefit that international standards development organizations like ISO bring to the industry. These agencies invest time and resources into evaluating and approving standards that will impact and improve industry practices. Incorporating internationally accepted methodologies into laboratory standard operating procedures brings several advantages.
This point is highlighted by the prevalence of globalization in today's pharmaceutical industry, with an estimated 20-25 percent of RandD investment spent on outsourcing. As more and more companies contract key laboratory operations from basic RandD through clinical trials and manufacturing, standardized methodologies become more critical. Laboratories across borders and oceans need to communicate in the same language using the same methodologies. Companies are opting for internationally recognized technologies and methods in order to facilitate compatibility among laboratories.
Laboratories across borders and oceans need to communicate in the same language using the same methodologies. Companies are opting for internationally recognized technologies and methods in order to facilitate compatibility among laboratories.
Ease of method transfer is also necessary. To seamlessly move projects from the research laboratory to the clinical trial stage or to processing facilities, operations in each facility must be harmonized. This can be achieved with accepted procedures.
Laboratories can also reduce risk by implementing a proven and internationally accepted quality assurance technology. This will prove useful during regulatory audits, in building client and consumer confidence and in striving to comply with cGMP and cGLP regulations and to ISO 17025, the international laboratory quality standard for calibration and testing. These standards support the preferential use of standard methods such as the photometric approach.
Integrating ISO-approved standards can also be leveraged as a first-mover's advantage over competition. While American pharmaceutical laboratories have traditionally turned first to the FDA for guidance, American regulations are evolving towards greater harmonization with their international counterparts. For example, the laboratory quality standard ISO 17025 was initially adopted most widely in Europe, but, stimulated by international treaty, has become the standard for American food testing laboratories. It is also being adopted on a voluntary basis throughout the FDA's own laboratory network. ISO's adoption of the photometric method for liquid delivery calibration is predicted to be followed by broad American acceptance. U.S. laboratories can act now to mold their laboratories to ISO standards and stay ahead of the competition.
Productivity Enhancing
Even slight volumetric discrepancies can compromise laboratory data integrity, leading to higher costs associated with remedial actions, useless data and inefficiency. In the ever-growing push for enhanced productivity, pharmaceutical laboratories are seeking to maximize performance of their liquid handling instrumentation. ISO has validated a new tool to do so, standardizing the photometric method and noting that it is particularly well suited for calibration of low volumes.�
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