Analytical procedures are necessary to ensure the identity, strength, quality, purity, and potency of a drug substance and drug products. In order to file a substance for commercialization with the FDA, a manufacturer must include a full description of the manufacturing process, including the analytical procedures that prove the manufactured product meets prescribed standards.
Early in the development of new analytical procedures, the choice of methodology is selected based on the intended purpose and scope of the analytical method. Parameters that are evaluated during method development are specificity, linearity, limits of detection (LOD) and limits of quantitation (LOQ), range of accuracy, and precision.
Since the FDA does not set specific rules about how analytical methods are undertaken – or to what extent – the choice of qualifying or validating analytical methods lies with the sponsor and its contract manufacturing organization (CMO). This article provides some insights and lessons learned about different approaches for qualifying or validating analytical methods.
When a manufacturer qualifies an analytical method, it is simply assessing that it is suitable for its intended purpose. It compares specific samples of the compound to a standard one to test its reproducibility. Many companies choose to conduct this process early in pre-clinical stages in order to the determine the feasibility of the API or generic compound. This process usually takes a little more than one week to complete, at a cost generally in the $12-15K range.
Analytical procedures in the early stages of method development are initially developed based on a combination of an understanding of the basic methodology and prior experience. Experimental data from early procedures are often used to guide further development.
In early stages of process research and pre-clinical development, it’s important to qualify your methods, but often that is all that is necessary. It’s critical, however, to validate your analytical methods in later stages – Phase II and Phase III when you are getting closer to filing for FDA approval.
While qualification of analytical methods and validation of analytical methods both work to prove that the method is suitable for its intended purpose, they differ in terms of the depth and robustness of the studies.
Validation most often occurs in later stages of clinical development – Phase II/III. At this stage, validation is critical, since the FDA won’t accept anything short of fully validated methods. The FDA publishes “guidance” information of what is considered acceptable criteria for commercialization, and the manufacturer must prove that its methods meet that guidance. As part of validation, the manufacturer develops a protocol that proves that no matter what quality of sample comes in it will get valid results – and it is proving this scientifically. It typically takes three weeks to validate a single method, at a cost in the range of $25-30K.
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A key analytical technique employed in an analytical laboratory is chromatography. In chromatography, organic and inorganic compounds are separated so that they can be analyzed and studied to determine what makes up that compound. In this way, scientists measure and validate the level of impurities in a compound. At PCI Synthesis, this is the main method we use to measure purity and assay of our compounds. It is our main analytical technique and requires the development of robust protocols and the ability to execute those protocols and document them.
While method validation is necessary before commercialization, companies often grapple with whether to also qualify the method in early stages to be as thorough as possible, and avoid surprises in later development stages.
Some companies also choose to go straight to validation of methods in early stages, jumping over qualification stages. This is often the case when developing generic APIs or NCE’s where we need to prove chemical equivalence. In other situations, however, validating methods in early stages can be overkill. The decision really boils down to cost. Many smaller biotech companies with limited budgets may want to simply qualify methods and only undertake validation when it is required for later phases of clinical development or commercialization.
While there’s no clear-cut answer as to whether a company should qualify or validate its analytical method, given the growing regulatory scrutiny, and depending on how much money a company has to spend, it’s sound to be as thorough as possible in order to be in the best possible position when the FDA reviews its filing. Many early-stage projects fail in clinical trials, so anything that can possibly help to beat those odds is prudent.
If you’re interested in learning more about process validation, check out our article here. Also, please contact us here: http://pcisynthesis.wpengine.com/contact-us/get- in-touch/.