As per ICH Q2(R1), precision is defined as below,
“The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.”
Precision should be investigated using homogeneous, authentic samples. The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of variation of a series of measurements.
Precision may be considered at three levels- repeatability, intermediate precision and reproducibility.
Repeatability
Variation that occurs when repeated measurements are made under absolutely identical conditions such as, same analyst–same instrument-same lab-same day.
Reproducibility
Variation that occurs when different conditions are used to make the measurements such as, different analyst–different instrument–different lab-different day.
Intermediate precision
Variation that occurs when different conditions are used to make the measurements such as, different analyst–different instrument–different day.
Note: intermediate precision is performed within same lab, or the lab that was used for repeatability.
In this article I will walk you through how to perform precision for various analytical tests such as assay, dissolution and related substances.
A. Precision for Assay:
a. Precision for API: Precision for assay of API is conducted by measuring %RSD (variance) for assay values from 6 test preparations. The test solution must be prepared by using homogeneous sample. Generally, the %RSD for 6 assay determinations of less the 2.0% is accepted.
b. Precision for finished product: Precision for assay of finished product such as tablets, capsules, creams etc. is conducted by measuring %RSD (variance) for assay values from 6 test preparations. The test solution can be prepared by using homogeneous finished product sample. In case if finished product sample is not available, the precision sample can be prepared as below,
- by mixing API with placebo as per the manufacturing formula.
- by mixing API with excipients as per the manufacturing formula.
Generally, the %RSD for 6 assay determinations of less the 2.0% is accepted.
B. Precision for Dissolution:
a. Precision for IR product: Precision for dissolution of IR product is conducted by measuring %RSD (variance) for dissolution values from 6 test preparations. The test solution can be prepared by using finished product sample. In case if finished product sample is not available, the precision sample can be prepared as below,
- by mixing API with placebo as per the manufacturing formula.
- by mixing API with excipients as per the manufacturing formula.
Generally, the %RSD for 6 dissolution determinations of less the 5.0% is accepted.
a. Precision for MR product: Precision for dissolution of MR product is conducted by measuring %RSD (variance) for dissolution values from 6 test preparations. The test solution can be prepared by using finished product sample. Generally, the %RSD for 6 dissolution determinations of less the 5.0% is accepted. The %RSD of drug release at last time point is considered for precision study. For example, if 2hr, 10hr and 20hr are the time points, then %RSD at 20th hour drug release must be considered for calculation of precision.
C. Precision for Related Substances:
a. Precision for API: Precision for related substances of API is conducted by measuring %RSD (variance) for impurity results from 6 test preparations. The test solution must be prepared by spiking known impurities into API to get concentration of impurities at their respective release specification level. In case if impurities are not available, and if test preparation contain impurities above LOQ- then method precision can be conducted using as such test solution. The precision study may not be possible if test solution does not have impurities above LOQ and impurity standards are also not available.
Generally, the %RSD for 6 determinations of less the 15.0% is accepted.
b. Precision for finished product: Precision for related substances of finished product is conducted by measuring %RSD (variance) for impurity results from 6 test preparations. The test solution must be prepared by spiking known impurities into finished product to get concentration of impurities at their respective release specification level. In case if finished product is not available, precision can be conducted by spiking impurities into mixture of API and placebo with similar composition to that of sample.
Generally, the %RSD for 6 determinations of less the 15.0% is accepted.
Note: The precision for impurities are performed at lowest specification, between release & shelf life specification. Most of the times, the release specification is found to be lowest specification and hence the same is recommended. The lowest specification comes with lowest concentration and hence with lowest response. The lowest response always leads to highest response variability and hence, if the method is found precise at lowest specification (release specification), it will also be precise at highest specification level(shelf life specification).Therefore, separate precision study with concentration at shelf life specification is not necessary.
Defining concentration of impurities for Related Substances precision:
Let us take a hypothetical example to understand how concentration for impurities are identified.
Assume that the concentration of standard and sample is 1ppm and 500ppm respectively. The release specification for impurity A, impurity B and impurity C is NMT 0.2%, NMT 0.5% and NMT 1.0% respectively. (NMT stands for Not More Than)
Step-I: Convert limit from % to ppm for known impurities. To convert the limit from % to ppm, you need to consider sample concentration as 100%.
Hence 100% = 500 ppm
Therefore 0.2% of impurity A= 1 ppm of impurity A (just do simple cross multiplication)
Similarly, you will understand that the limit for impurity B and impurity C are 2.5ppm and 5 ppm respectively.
Step-II: To prepare precision sample, you need to spike impurity in such a way that the final concentration of impurity A, impurity B and impurity C will become 1ppm, 2.5ppm and 5ppm respectively. Care must be taken to compensate the quantity of any known impurity present in test.
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