Drug product linearity

For the determination of potency assay of a drug substance or a drug product, the usual range of linearity should be +20% of the target or nominal concentration. For the determination of content uniformity, it should be 30% of the target or nominal concentration. Figure 3 illustrates the linearity of a sample set of data. 

Experimental Requirements. Solutions of known concentrations are used to determine the linearity. A plot of peak area versus concentration (in percent related substance) is used to demonstrate the linearity. Authentic samples of related substances with known purity are used to prepare these solutions. In most cases, for the linearity of a drug product, spiking the related substance authentic sample into excipients is not necessary, as the matrix effect should be investigated in method accuracy. 

Accuracy. Sample solutions of known concentration (e.g., spiked placebo) are used for the accuracy determination. Experimental work may be organized so that the same stock solutions are used to prepare both linearity and accuracy solutions. The accuracy solution must be exposed to normal test conditions (e.g., mixing in a heated dissolution vessel). Determine any bias that is caused by the sampling and analysis of the solutions. If a dissolution profile of the drug product is required, accuracy determinations at different concentrations of the required profile will need to be performed (e.g., at 40, 75, and 110% of theoretical release). The results are reported as percent theory. 

The range is derived from the linearity and accuracy of the method and will be demonstrated for compound X over the range of 80-120% of the nominal assay concentration, and for related compounds over the range of 0.1-2% of the related compound in the drug product. 

Shinozuka et al. [91] developed a sensitive method for the determination of four anthranilic acid derivatives (diclofenac sodium, aluminium flufenamate, mefenamic and tolfenamic acids) by HPLC procedure. The four drugs were converted into methylphthalimide (MPI) derivatives in a constant yield by reaction with /V-chloromethylphthalimide at 60°C for 30 min. The production of the MPI derivatives were confirmed by mass spectrometry. The MPI derivatives of the four drugs were separated by HPLC using a C-18 bonded phase LiChrospher RP-18 column (250 x 4 mm i.d.) with acetonitrile-water (80 20, v/v) as mobile phase. The flow rate was 0.8 mL/min. The UV absorbance was measured at 282 nm. The calibration curves of the MPI derivatives of the drugs were linear from 1.0 to 5.0 pg/rnL. The detection limits of the four drugs were 0.5-5 ng. The extraction procedure for the four anthranilic acid derivatives added in the plasma and urine was performed by using Extrelut 1 column. Yields of column extraction of 100 pL of plasma and urine samples (containing 0.5 pg of anthranilic acid derivatives) with 6 mL of ethyl acetate were 84-106%. 

The above statement has lot of details in reference to what is a SIM The statement starts with method validation (refer to Chapter 9). Next, most methods need to be specific (specificity, resolution of active from related substances, peak purity), reproducible (precision), quantitative (recovery, linearity, LOD, LOQ), and able to monitor a change in chemical, physical, and/or microbiological properties of drug products over time (refer to sections on stability testing and mass balance). 

As indicated in the validation section for drug substance, the purpose of this test is to demonstrate that low-level linearity can be routinely achieved for drug product evaluation. 

LOD/LOQ/Low-Level Linearity for Specified Impurities in Drug Product (Spiking Experiment)... 

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