In his 1996 review of analytical method validation, author Mark Green notes, “Doing a thorough method validation can be tedious, but the consequences of not doing it right are wasted time, money, and resources.”
Over the past few decades, regulatory and standardssetting organizations have revised their validation guidances to reflect current thinking, but the definition of analytical method validation has remained the same: “the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications.”
Built into this definition is an implicit component of risk. For an analytical process to “meet the requirements for the intended analytical applications,” analysts must consider the purpose of the assay, inherent analyte and method variability, and the overarching “requirement”—for example, an end product’s use. Within this framework, pharmaceuticals are an excellent model for analytical method validation, given that industry’s regulatory rigidity.
USP (Rockville, MD), the premier pharmaceutical standards-setting organization, lists the goals of validation as quantification of a method’s accuracy, precision, specificity, detection and quantitation limits, linearity, range, and robustness. Industries, and groups within industries, might be more interested in robustness than accuracy or in precision more than robustness. It all depends on meeting “the requirements for the intended ... applications.”
Ed Price, CEO of contract drug manufacturer PCI Synthesis (Newburyport, MA), has cataloged the top 10 questions to ask before undertaking analytical method validation. Based on these considerations, Price recommends that validation experts think ahead to future method testing. “It’s critical... to prepare for further review of all analytical methods developed... The most effective analytical method development assures that lab resources are optimized and that the methods developed can be validated at each progressive step in the process. If changes to a method are required, it’s best to do so, and document the changes, before moving on to the next validation step.”
Price also stresses the importance of method optimization in order to squeeze all potential benefits from the selected analytical platform.
Revolution: Risk-based validation
Several standards and government organizations influence pharmaceutical method validation. The U.S. Pharmacopeial Convention sets general specifications for active drug compounds and finished products and describes the types of tests and instrumental methods drug makers must employ to meet those specifications. The pharmaceutical companies work out the specific method, which, per USP guidelines (themselves derived from ICH guidances), are established through a validation process. “Every single method included in the USP must be validated,” says Horacio Pappa, director at USP.
USP’s validation guidelines have served the pharmaceutical industry for nearly three decades. But given the age of USP’s validation guidelines and what has been occurring in the larger industry, USP began to consider whether established validation protocols were still applicable. “Can we continue using 30-year-old concepts in light of technical advances?” Pappa asks. “There is clearly room for discussing a new approach to validation.”
Quality by design (QbD) refers to the practice of monitoring quality during production rather than “testing in” quality through post-production assays. QbD was originally applied to product manufacturing, which makes sense, since “quality” is a concrete attribute.
Related Article: Quality By Design
“We started asking ourselves if the same concepts could apply to analytical methods,” Pappa tells Lab Manager. Like quality programs, method validation is not a discrete activity performed once and forgotten. “It exists, and is invoked, on a continuum through the method’s life cycle, which includes method development, qualification, and performance verification.”
The motivation behind rethinking method validation arises from the definition of validation as promulgated by the FDA, ICH, and USP: to demonstrate that a method is suitable for its intended purpose and it measures what you want to measure with appropriate accuracy and precision.
“That idea, although it falls under the official definition of validation, is not reflected in current guidances,” Pappa says. “The current guidances present validation in the form of a checklist. You perform the items on the list, and the method is officially validated. But it’s difficult to conclude after checking all the boxes that the method actually is suitable for intended use. We’re trying to put more emphasis on that demonstration.”
Pappa describes the revamped approach to validation as “a new concept, a journey, a work in progress that is centered on risk.” USP will communicate these recommendations to drug makers through its house organ, the Pharmacopoeial Forum, and through workshops where stakeholders will enjoy the opportunity to provide input. If the variability of a method is small compared with the specification, that method will work. “In this scenario, defining what is sufficiently accurate and precise becomes critical. Risk is a function of the method’s criticality.”
Risk-based validation injects understanding and science in what may previously have been blind adherence to protocol.
For example, many drugs under development today have a narrow therapeutic window, meaning the effective dose is not very different from the toxic dose. “Because assay results occur over a normal distribution, very likely a fair amount of product, which on average falls within specification, will fall below the lower specification range,” Pappa explains. Method validation should provide evidence that the method detects and quantifies those excursions from specifications.
According to Lisa Thomas, senior director, life science mass spectrometry at Thermo Fisher Scientific (San Jose, CA), many labs struggle to plan and execute analytical validation adequately. “Inadequate planning can potentially turn a 10-week validation into a 40-week process, resulting in substantial delays [in] the lab’s ability to process samples.”
Thomas cites expertise, time, and statistical confidence as negative factors affecting validation success.
“Finding scientists who understand quality management can be challenging, as is finding personnel who understand instrumentation and the science sufficiently to conduct proper method assessment and validation. Small-to-midsize organizations have difficulty dedicating time to method validation, since that activity competes with the daily lab operations.”
Related Article: How to Develop Validated HPLC Methods
Thomas is open to a risk-based approach to validation, calling it a way to ensure the appropriate amount of testing is reflected in the potential implications of not testing. “Over the years, I’ve seen the extremes; too little validation may come at a financial cost in terms of product recalls or tarnishing brand reputation, while too much validation may impede employee effectiveness, innovation, and responsiveness.” For several years, GAMP (good automated manufacturing practices) and guidance bodies have evolved their thinking toward risk-based validation.
A risk-based approach is very much based on the lean principle of keeping only those processes and activities that add value. Pharmaceuticals have some of the best quality practices in place due to the potential effect of their products on patient safety, but generally their operations are not lean, according to the management school definition of the term. “For many contract testing labs and clinical reference labs, lean procedures enable them to drive their cost per test down to maintain market competitiveness—often leading the way for lean best practices,” Thomas says.
Only a minimum?
In a recently published application note, scientists from Waters (Milford, MA) demonstrated the validation of a method for detecting metoclopramide, a drug for gastrointestinal reflux, and “related substances,” presumably side products from the drug’s manufacture. The Waters team was looking specifically for assay linearity, detection and quantitation limits, accuracy, repeatability, intermediate precision, specificity, and robustness.
According to Margaret Maziarz, an app note co-author and a principal scientist at the company, those validation objectives reflect regulatory guidelines from ICH, USP, and FDA, “but those are only the minimum validation goals for analyzing this drug by UPLC.” Analysts should be prepared to validate supporting processes that feed directly into the method being validated—think of an inverted pyramid with preparatory processes funnelling into the main act, which is assaying a drug. “Preparing metoclopramide for analysis involves filtration to remove particulates, excipients, and colorants, so validation of filtration should also occur to assure maximum recovery of the drug.”
Long-term stability or storage is a huge quality metric for drugs and other perishable products. For analytical methods, however, analysts also need assurance that their samples, standards, and reagents pass the time test, albeit for a shorter term than for traditional stability assays. “Again, the goal is to ensure that the LC method, including the instrument, provides the expected results reproducibly,” Maziarz explains.
Maziarz was reluctant to discuss risk-based or purpose-based validation, which is understandable given the negative inertia risk-based manufacturing faced when the FDA was pushing this idea a decade ago. To the question of whether validation might be relaxed in certain less-risky situations, she responded, “To be sure you’re in compliance, simply follow the regulations, whatever they are. If you have questions, you can ask regulators or standards organizations. For pharmaceutical products, there is no such thing as a reduced need for validation. Risk-based validation is a great idea, provided the risk analysis is sound. That may be down the road at some point, but that is for USP and FDA to decide.”