New FDA Guidance on Analytical Methods Provides General Approach, but Few Details

New FDA Guidance on Analytical Methods Provides General Approach, but Few Details

The United States Food and Drug Administration (FDA) has issued a new guidance document, Analytical Procedures and Method Validation for Drugs and Biologics. The new document, dated July 2015, supersedes the draft guidance of the same name that was published on February 19, 2014. It also replaces the 2000 draft guidance Analytical Data for Methods Validation and the 1997 Guidelines for Submitting Samples and Analytical Data for Methods Validation. It complements the International Conference on Harmonization (ICH) guidance Q2(R1), Validation of Analytical Procedures.

The guidance document provides recommendations for submitting analytical procedures and method validation data to the FDA to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. It applies to drugs covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs) and amendments to those applications. The guidance does not address method validation for investigational new drug applications (INDs).

The guidance is, however, quite general in nature, and is shorter than the 2000 draft document. Anyone hoping for specific recommendations on topics such as which methods to use will be disappointed.

Drew N. Kelner, who recently retired from Amgen after spending 25 years in the biopharmaceutical industry leading early and late-stage analytical development organizations at Bayer and Amgen, says it really isn’t feasible for the FDA to provide detailed recommendations about analytical methods for biopharmaceuticals.

“Every time guidance is issued we hear talk about the ’gaps,’ generally centered on the desire for more specificity and detail around methods and technologies that should be applied for product testing and characterization,” he said. “In my view, there is no true gap, because a significant amount of latitude is required from a regulatory standpoint.”

This need for regulatory latitude is a direct consequence of the fact that the technology and engineering underlying the field have advanced at such an impressive rate, he added. “The rate of change has been so rapid, in fact, that any specific guidance that is provided may be outdated by the time it is published.” 

Kelner also commented that it is simply not possible for the regulators to know what's coming next into clinical development. “In the past few years, we have seen new types of products introduced into the clinic, such as exciting new potential cancer therapies like antibody­–small molecule drug conjugates, bi-functional T-cell engagers (BITEs), and engineered viruses,” he said. “I don’t think we can even predict what we might be dealing with a decade from now.” 

And just as the forms of biotherapeutics have evolved, so have the capabilities of analytical instruments. “In the past two decades, we have seen technological leaps in protein mass spectrometry that approximate an order of magnitude improvement in sensitivity and resolution every 4-5 years,” noted Kelner. “The evolving technology is applied to product characterization and quality control testing, and the results of these efforts are only seen by the regulators after they have been submitted to the agencies.”

While the guidance does mention design of experiments (DOE) and the use of a risk-based approach to product testing, both principles of the Quality by Design (QbD) paradigm, Kelner would have liked to have seen more discussion of QbD in the new guidance, since this approach has profoundly impacted biopharmaceutical development in recent years, as the tools have emerged to provide data that can be used to link the analysis of product attributes with their biological relevance. 

“We can often detect protein variants down at the 0.1% level, and we can identify every host cell protein down to the single-digit parts-per-million level,” he says. As a result, the question is no longer what can be measured; it is what should be measured. This is the essence of Quality by Design, and the best means currently available to ensure patient safety and efficacy.”

“The most effective regulatory approach for the CMC [chemistry, manufacturing, and controls] section is based on a strong understanding of the molecule and process, with the application of appropriate risk analysis tools to provide a probabilistic estimate of process and attribute risk,” he says. “When it comes to the CMC section of the marketing application, there is nothing better than presenting a thorough understanding of the biochemical, biophysical and biological properties of the molecule. That is the path to regulatory success.”