Dose Formulation Analysis: Testing Concentration, Specificity, Homogeneity, and Stability
Dose formulation analysis is performed to assess test article concentration, formulation homogeneity, and formulation stability. Currently, there is limited regulatory guidance on preclinical method validation for formulation sample analysis. However, several stipulations are necessary for drug product/formulation testing following dose formulation analysis GLP regulations, and these methods can be validated following the FDA’s bioanalytical guidance.
The AAPS whitepaper “NonClinical Dose Formulation Analysis Method Validation and Sample Analysis” (2010) refers to the formulation analysis practices required for GLP toxicology studies. The primary differences in bioanalytical and drug product validations typically involve acceptance and stability criteria, since formulations usually show less analytical variability and are stored under differing conditions.
Dose formulation analysis for regulated preclinical and clinical studies is conducted in compliance with one or more of the following: US Food and Drug Administration (FDA) Good Laboratory Practice (GLP) regulations as per 21 CFR part 58, the European Medicines Association (EMA) Principles of Good Laboratory Practice, the Japanese Ministry of Health, Labor and Welfare (MHLW) Number 21, and the FDA Guidance for Industry: Bioanalytical Method Validation.
Dose Formulation Analysis: From Drug Discovery and Preclinical to Clinical Phases
Drug Discovery Formulation Sample Analysis
Dose formulation analysis during early drug discovery determines the correct dosage for proper concentration, homogeneity, and stability of the test article in any vehicle. Formulation analysis of several vehicles during exploratory pharmacokinetics or disease model efficacy testing could help pick the best alternative for a novel compound or class of compounds. Similarly, salt forms or prodrugs of the potential drug can be evaluated to decide whether these forms yield better solubility for improved in-vivo absorption.
In early discovery testing, the formulation analysis needs to only sufficiently demonstrate therapeutic delivery for supporting proof-of-concept and lead target identification. The robustness of these formulations for accuracy, homogeneity, repeatability, and stability, is not typically considered until regulated preclinical toxicology data gets generated.
GLP Formulation Method Validation
Regulated formulation analysis studies during preclinical and clinical development require method validation. GLP formulation method validation experiments span the anticipated dose concentration range and include testing for accuracy, precision, specificity, curve linearity, and analyte stability. Generally, homogeneity in formulation analysis is tested for the first test batch low and high dosage form concentrations and if there is a significant change in batch size. Homogeneity is usually tested by assessing replicate samples from the bottom, middle, and top strata of the dose form preparation vessel. Stability in formulation analysis is tested by collecting samples from the lowest and highest dosage concentrations at a minimum. Replicate samples for stability are stored at the conditions for in-life study and evaluated for the time from preparation to final dose.
Preclinical (or nonclinical) dose formulation analysis is required in all regulated studies to assess drug safety. The primary purpose of preclinical toxicology studies is to establish safety margins for clinical studies. Formulation sample analysis following GLP formulation method validation in regulated studies, in turn, verifies test article concentrations in the formulations for preclinical toxicology studies.