PK Assay Validation and Regulatory Compliance

Validated pharmacokinetic assays for evaluating drug absorption, distribution, metabolism, and excretion in biological matrices are crucial for successful nonclinical and clinical biopharmaceutical studies. Validated pharmacokinetic studies provide vital data to support drug efficacy and safety. Today, pharmacokinetics labs employ a fit-for-purpose approach to determine appropriate levels of method validation. The extent of method validation should match the intended application of a pharmacokinetic study. 

PK sample analysis is critical for regulatory approval, labeling, and safety. PK assays are hence crucial for BLA, NDA, and ANDA submissions. Often, exploratory pharmacokinetic testing does not require such stringent validation strategies. The fit-for-purpose approach applies to drugs, metabolites, and biomarkers. Pharmacokinetic labs involved in toxicological studies for regulatory applications should adhere to good laboratory practices. Besides, bioanalytical methods such as the HPLC test for evaluating pharmacokinetic properties should fulfill specified 21 CFR 320 BABE requirements. The current article discusses PK assay validation and its regulatory compliance. 

Pharmacokinetic studies

Today, researchers are often confused between regulatory compliance and bioanalytical guidance documents for drug development studies such as pharmacokinetic and pharmacodynamic evaluations. It is a common misinterpretation that GLP and GCP compliance for PK biomarker testing needs full validation conforming to FDA EMA analytical method validation guidelines. However, this is not the case.

The US FDA guidelines for analytical method validation recommend general considerations for method validation studies. These recommendations can be modified or adjusted based on the type of analytical method used for analysis. 

Regulatory guidance documents are crucial for PK assay validation. They provide a framework to ensure experimental techniques are fit for the intended applications. However, it is critical to understand that regulatory guidance documents are advisory, but they are the gold standard for bioanalytical testing. 

Good laboratory practices are a system regulating organizational processes and experimental conditions for performing nonclinical and environmental safety studies and their adequate planning, performance, monitoring, recording, and reporting. Good clinical practices are international scientific and ethical quality requirements for designing, performing, recording, and reporting clinical studies involving human subjects. 

GxP regulatory documents include very little information about the extent of method validation or approach to sample analysis. They are quality management systems covering different study types. Hence, the extent of method validation should be based on study objectives and not on GLP/GCP compliance. Understanding the intended application of PK assay is critical to ensure its fit-for-purpose alignment. 

Full method validation can support nonregulatory studies. However, a qualified method is needed for regulatory complaint study when claiming compliance from the generated data. The qualified method is one where researchers understand critical parameter variations. 

Additionally, the same study may have different objectives. For example, a GLP tox study in rodents obtained plasma samples for TK analysis or tissue samples for checking the presence of a drug product. A full validation is required for plasma samples, while qualification is performed for tissue samples. Notably, no regulatory guidance mentions the extent of method validation required to demonstrate metabolites in clinical samples. 

In Conclusion

pharmacokinetic studies are crucial to determine the ADME properties of a product. However, adequate method development and validation are critical for generating reliable, reproducible, and accurate results. 

Must Read: Quantifying Bictegravir in Human Plasma: A Comprehensive Step-by-Step Guide to LC-MS Method Development and Validation

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