Analytical development and/or QC groups at early-stage pharmaceuticals and biopharmaceuticals often ask themselves about the level of level of confirmation of suitability required for their methods. Often the term ‘validation’ is used without understanding the full implications of the term. Sometimes, the terms validation, qualification and verification are used interchangeably. While ‘validation’ is well understood and recognized across the industry, the other terms are sometimes used in wrong context.
In early-stage pharmaceutical development, e.g., in Phase I clinical trial, a full validation of a method may not be possible or even prudent. At this stage, the manufacturing process is still under development and not locked. If the manufacturing process is not locked then a full validation of those methods that are tied to that process may not be well reasoned. However, it is expected that certain aspects of validation parameters are evaluated and verified at this stage. FDA guidance for industry for Phase I investigational Drugs (although quite dated), states that “Laboratory tests used in manufacturing (e.g., testing of materials, in-process material, packaging, drug product) should be scientifically sound (e.g., specific, sensitive, and accurate), suitable and reliable for the specified purpose.” Until recently available ICH guidelines focused on validation of Analytical methods at GMP stage suitable for Phase III and beyond through ICH Q2(R1), Validation of Analytical Procedures. With the new draft revision of this guidance (ICH Q2(R2)) and introduction of ICH Q14, a systemic guidance for the analytical lifecycle process is provided. Certain aspects of validation parameters can be evaluated during method development stage and may be used during validation. In fact, the draft Q 14 guidance suggests “In general, data gained during the development studies (e.g., robustness data from a design of experiments (DoE study)) can be used as validation data for the related analytical procedure performance characteristics and does not necessarily need to be repeated.” For analytical methods used for early phase products, a risk-based approach should be taken for selecting which methods are to be validated first. For example, since ‘safety’ is the primary focus at Phase I, any methods that can confirm the batches have a reliable safety profile (such as purity / potency of the active ingredient) should be prioritized over others. In addition, any other stability indicating tests should be also considered. Now, if you are not performing ‘full validation’ per ICH Q2 at this stage, it is prudent to reserve the term ‘Validation’ for later stage (Phase III and commercial). A term such as ‘Qualification’ may be used.
The term ‘Verification’ should be used when demonstrating the suitability of a previously validated method or compendial methods for the product matrix. The suitability of the methods applies to the products that are produced, which means if there are changes in the manufacturing process or source materials, any early Phase suitability may not be valid and must be evaluated again under change control. In fact, all methods that are Qualified or Validated at all stages must be evaluated under change control whenever there are changes to the process or material. What about adapting off-the-shelf pre-approved test kits (e.g., endotoxin test kit)? Usually, the vendor will recommend verifying certain parameters and assessing the suitability of the kit for the target product before using the kit in productive environment. Such parameters and any additional parameters defined in the method validation SOP of the organization must be tested and documented. This activity can also be defined as Verification.
In summary, all term related to standardization of analytical methods must be defined in a governing SOP. For early-stage pharmaceuticals, where all parameters as defined in ICH Q2 are not examined yet, the term ‘Validation’ should not be used. A CMC policy for phase appropriate Analytical Procedure Development following the draft ICH Q14 and ICH Q2 (R2) will be highly beneficial.
If you have any questions relating to your site’s Phase Appropriate CMC development Program or Analytical Method Lifecycle Management Program, please contact us at LCS@LachmanConsultants.com.