Bracketing

Certified reference material (CRM)

A primary reference material or substance, accompanied by a certificate, one or collective agreement usually a number of laboratories

Sequence-control sample

A sample with an extreme content of the analyte (but falling within the working range of the method) -It is inserted at random in a batch to verify the correct order of samples. -Useful for long batches in automated analyses Very effective is the combination of two such samples: one with a high and one with a low analyte content.

Control sample

A sample with an extreme content of the analyte (but falling within the working range of the method).

Blind sample

A sample with known content of the analyte. This sample is inserted by the Head of Laboratory or the Quality Officer in batches at places and times unknown to the analyst. The frequency may vary but as an indication one sample in every 10 batches is given

Reference material (RM)

A secondary reference material or substance, property values are accurately determined by a number of laboratories For certain properties a "true" value cannot even be established as the result is always method-dependent

Bracketing ctd.

Bracketing can be applied to studies with identical or closely related formulations for example --Filling of varying capsule sizes from the same powder blend to give variable dosage strengths --Where powder blend are identical in qualitative terms but vary in quantitative composition (this should be justified) Bracketing is not intended for powder blend that vary in qualitative terms (other excipients)

Bracketing

Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors -strength, -container size and/or -fill are tested at all times as in a full design. The design assumes that the stability of any intermediate level is represented by the stability of the extremes tested.

Bracketing

Compliant sample and standard management program, concept of raw data within the pharmaceutical industry

Potential risks in matrix design

Due to the reduced amount of data collected, a matrixing design on factors other than time points generally has: --Less precision in shelf life estimation --Yields a shorter shelf life than the corresponding full design.

Applicability and Degree of Reduction ctd.

In general, a matrixing design is applicable if the supporting data indicate predictable product stability. Matrixing is appropriate when the supporting data exhibit only small variability. Where the supporting data exhibit moderate variability, a matrixing design should be statistically justified. If the supportive data show large variability, a matrixing design should not be applied.

Matrixing

Matrixing uses a statistical design as the basis for testing only a selected subset of factors for example -dosage strength - package size - Filling at a specific time point

Potential risks in matrix design ctd.

May have insufficient power to detect certain main or interaction effects, --thus leading to incorrect pooling of data from different design factors during shelf life estimation. If there is an excessive reduction in the number of factor combinations tested and data from the tested factor combinations can not be pooled to establish a single shelf life, it may be impossible to estimate the shelf lives for the missing factor combinations.

Types of sample materials

Test sample Spiked sample Blind sample Control sample Sequence-control Certified reference material (CRM) Reference material (RM)

Types of sample materials ctd.

Test sample --The material to be analyzed, the "unknown". Spiked sample ---A test material with a known addition of analyte. ---The sample is analyzed with and without the spike to test recovery . ----It should be a realistic surrogate with respect to matrix and concentration. The mixture should be well homogenized.

Types of samples ctd.

The requirement "realistic surrogate" is the main problem with spikes. Often the analyte cannot be integrated in the sample in the same manner as the original analyte, and then treatments such as digestion or extraction may not necessarily reflect the behaviour of real samples.

Matrixing ctd.

These subsets of samples vary from one time point to the next. -- A general rule requires that all factors be tested at the beginning and end of the shelf life. ---This also applies for the 12-month time point if the data of a comprehensive long-term stability study are still not available.

Types of sample materials ctd.

Types of sample materials ctd.

Types of samples ctd.

Types of samples ctd.

Applicability and Degree of Reduction

When a matrixing design is planned there should be -Knowledge of data variability -Expected stability of the product -Availability of supporting data -Stability differences in the product within a factor or among factors and/or -Number of factor combinations in the study