Matrices and Bracketing in Process Validation

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􀂇 Product packaging, such as where only a minor adjustment in packaging
parameters is required to accommodate different bottle heights or dosage
counts.
Matrixing across different products may be applied to the packaging validation of the
final dosage form, for example to evaluate the packaging of different products in a
common packaging presentation. As with other uses of bracketing and matrixing, the risk
of using this strategy for the potential products encompassed by the matrixing plan
should be considered, documented and approved.
The use of bracketing/matrixing for the validation of a manufacturing process across
different products should be approached with caution because of the risk of overlooking
other possible affects of the change. Use of this type of bracketing/matrixing requires a
good understanding of the processes involved and the risks being assumed. For example,
in the evaluation of a change of a critical material for different products, the excipient
interactions, critical process parameters and critical quality attributes (CQAs) are not
necessarily the same for each product. The effect of the change in the CQAs may be
different for each product. A product sensitive to the change may experience a failure in a
CQA (e.g. dissolution) while in a case of a product not sensitive to
the change, it may experience no effect at all in its CQAs.
To obtain the maximum benefit with minimum risk from bracketing and matrices, it is
necessary to have a well-developed understanding of the impact of critical process
parameters on critical quality attributes. There should be a documented and justified
rationale that explains why one set of test conditions (e.g., manufacturing process,
product presentation, etc.) is representative of one or more related test conditions.
Typically, the rationale is addressed by selecting parameters and/or products that
represent the edges of a range or 􀂳worst case􀂴 of allowable conditions. The rationale and
justification for the bracketing/matrixing strategy to be used in validating a process
should be provided in the validation protocol, or in another document referenced in the
protocol.
Depending on the circumstances, prospective and concurrent validation approaches may
be used for validating a process using bracketing or matrixing. If a concurrent approach is
used, an interim report provides a summary of the results obtained for a product batch, in
order to justify the validation and release of one of the product presentations within the
bracket/matrix. This approach may also assist in approving the manufacturing and/or
release of additional batches of a particular presentation. At the completion of the
validation, the validation report will address all batches.
At present, some regulatory authorities may not accept the use of bracketing or matrixing
for validation. Japan, for example, currently requires that all combinations be validated.
The following examples include possible matrixing/bracketing approaches. There may be
other acceptable approaches.