• Sep 16, 2021
  • Quality Assurance and Methods Compliance
  • By Shane Hill

What Is Method Validation and Might You Need It?

By Shane Hill

Confidence, reliability—ultimately peace of mind. In short, this is the takeaway following an analytical test method validation.

Do you work in pharmaceuticals, cosmetics, or the environmental realm? All of these fields, and more, benefit greatly from the method validation process. While initially only a mused measure proposed by minds at the US Food & Drug Administration to enhance the integrity of pharmaceutical drugs in the 1970s, it rapidly became a codified and collective effort to improve general processes in manufacturing. Supply chain elements such as product filling and equipment sterilization caught immediate attention and were subjected to a validation metric whereby consistency of execution was paramount. Soon after manufacturing yields were tightened and made more reliable, the eyes at FDA deemed the validation process applicable to the granular level of characteristic tests for sample analysis techniques such as particle size distribution.

Test validation began to incorporate elements from the engineering world, such as the concept of “gauge R&R,” or more broadly termed, a gauge repeatability and reproducibility systems approach. In equipment design, being able to repeat a blueprint within tight specification and moreover reproduce it at another manufacture site was crucial. This same concept was extended to sample material testing in a wide variety of applications.

Particle Technology Labs has three general laboratory focuses: gas physisorption, particle size/count, and automated imaging analysis. In our current Good Manufacturing Practice (cGMP) abiding environment, each of these genres of sample testing follows a test method document, which chronicles appropriate settings and parameters for its respective analysis. Furthermore, it is tailored not only to client request, but to sample-specific request, all the while reflecting standard operating procedures.

Method Validations at Particle Technology Labs

Depending on your samples’ analytical background, a submission at Particle Technology Labs becomes routed through laboratory management to ensure an appropriate technique has been chosen based on request. From there, our clients fall into three distinct categories:

1. They do not have a test method for their sample and seek guidance on developing one
2. They have a working but albeit partial method
3. They have a formal method arriving with thorough vetting through previous means.

Regardless of category, any of these test method scenarios can be processed through validation—the only essential difference is the background evaluation depth necessary to arriving at a finalized test method document, ready to undergo validation.

History and context accounted for, the validation testing design itself is fairly straightforward and derived strictly from official guidances via sources such as the US Pharmacopeia and International Council for Harmonisation (of Technical Requirements for Pharmaceuticals for Human Use). USP <1225> Validation of Compendial Methods references typical testing characteristics such as Accuracy, Precision, and Ruggedness, as well as a host of other elements depending on application (e.g., Specificity or Linearity may only apply to certain instrument techniques). For the broadest scope of clients, the aforementioned three tests are the most commonly employed for end-use in preparation for a New Drug Application (NDA) for a company’s submission to FDA. What’s more, the ICH official document “Q2(R1) Validation of Analytical Procedures: Methodology” provides further insight regarding appropriate characteristic tests, going so far as recommending ideal data outputs for Accuracy, Precision, as well as addressing Robustness and System Suitability (which may ultimately be optional depending on method background).

Purpose of Test Methods Validation

A validation study is intended to demonstrate that a given analytical procedure is appropriate for a specific sample type.

• Accuracy testing is a staple inquiry of FDA—this characteristic illustrates an instrument’s ability to accurately produce data within a specified range of interest (however narrow or broad) by use of a certified reference material.

• Precision and Ruggedness testing serve to examine how repeatable the sample analysis can be, when especially subjected to variations such as a second testing day, a second chemist, or even a second instrument unit. To the extent applicable, acceptance criteria from USP or other guidance may be used from which to compare generated data. Ultimately, sample data is recommended to be evaluated comprehensively through statistical software (a prime example being JMP Discovery), to determine equivalencies and confidence intervals.

While validation is definitively required for a new drug application, it is also required following instances when a drug product happens to be altered or modified in any capacity. Even if a test method has historically undergone validative work, it may be necessary to repeat the entire study (“re-validate the method”) with the new sample variant to ensure its predictability long term. Moreover, with the burgeoning technology of today, analytical instrumentation is being updated and optimized constantly—re-validation is highly recommended and, in most scenarios, required when transferring to a newer generation of instrumentation. Over the past few years, a common example of this is witnessing customers updating their particle size methods from a Malvern Mastersizer 2000 to Mastersizer 3000, in which case a fresh validation is sought to perform full precision assessment on the newer unit. Nearly all regulatory departments file requisite change controls for such an endeavor, ultimately accountable to federal scrutiny; current assay data to demonstrate repeatability and ruggedness provides the assurance you’ll need.

At Particle Technology Labs, a method validation study carries a 6 to 8-week lifecycle. The effort is bookended by formal protocol and report, each of which is handcrafted by PTL in granular detail yet remains collaborative with respect to any client-directed feedback. All characteristic tests are executed by well-trained chemists, technically reviewed by highly qualified personnel, and beholden to quality-assured scrutiny ahead of client receipt. The end result of PTL’s validation process is to provide our clients with a finalized test method that has not only undergone rigorous testing schemes, but also has been vetted through statistical evaluation so as to offer predictability and therefore confidence in your results—whether for an NDA submission or simply to have confidence in consistency of your sample’s data.

Contact PTL’s Methods Department today, if you have a requirement for validation or even the mildest of interest otherwise—we’re here and happy to help!

By Shane Hill, Assistant Manager for Methods Compliance.

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