Bracketing and Matrixing Stability Design Generator (ICH Q1D)

About the Bracketing and Matrixing Stability Design Generator (ICH Q1D)

A stability programme for a product in several strengths and packs multiplies quickly: three batches of three strengths in three container sizes are 27 combinations, and eight time points make 216 tests at one storage condition. ICH Q1D allows two reductions. Bracketing tests only the extremes — the lowest and highest strength, the smallest and largest container or fill — and lets them represent the levels in between. Matrixing tests a selected subset of the combinations at each time point, a one-half or one-third reduction, while every combination is still tested at the start, at the end and at the last time point before submission.

Enter the batches, strengths, container sizes or fills and storage conditions with their time points, choose the reductions, and the page builds the design the way the example designs of Q1D are built, then checks it against the guideline: the extremes, the formulation and pack conditions for bracketing, the variability of the supporting data, three time points per combination in the first year, balance across combinations. The design applies the method you choose; your QA approves the result. The free preview builds the whole design and shows the combinations, which are bracketed, the time points every combination is tested at and every check with its verdict; the matrix itself, the reduction achieved, the samples and units per pull and the pull dates, the PDF and the workbook need an Ultimate pass.

Common uses

• Drafting the reduced design of a stability protocol for a new product in several strengths and packs.
• Working out how many units to place on stability and when each pull falls due.
• Checking a proposed reduced design against the conditions of ICH Q1D before it goes into the protocol.
• Explaining bracketing and matrixing with the guideline’s own examples.

How the design is built

• Bracketing (ICH Q1D 2.3, Table 1): with three or more strengths, or three or more container sizes or fills, only the lowest and the highest are tested, at every time point.
• Matrixing on time points (2.4, Tables 2 and 3a): each tested combination is put in a group by (batch + strength + pack) mod g, with g = 2 for one-half and 3 for one-third — exactly the assignment of Q1D Table 3a — and one group is left out at each intermediate time point, in a turn that runs on through the fully tested time points, as the key of Tables 3a and 3b does.
• Always tested: the initial and final time points and, at the long-term condition, 12 months or the last time point before submission; through the first 12 months every combination keeps at least three time points including the initial one, and at an accelerated or intermediate condition three including the initial and final ones (2.4.2). Where the turn would break that, the test is kept.
• Matrixing on factors (Table 3b): each batch leaves out one group of strength and container combinations, a different one in each batch, so every combination is tested on the other batches.

With these rules the page reproduces Q1D Tables 3a and 3b cell by cell. The guideline presents its tables as illustrations, not the only or the most appropriate designs: Table 2’s illustration groups its combinations differently after 12 months, and the page’s design removes the same number of tests (15 or 10 of 48).

When bracketing and matrixing apply

• Strengths: bracketing suits identical or closely related formulations (one blend in different fills, one granulation compressed to different weights); a changing ratio of drug substance to excipients needs a justification, and different excipients generally rule it out.
• Packs: one container closure system with either the size or the fill varying; when both vary, the largest and smallest may not be the extremes — compare wall thickness, closure geometry, surface area and headspace to volume and permeation per unit.
• Matrixing: appropriate with small variability of the supporting data, to be justified statistically with moderate variability, not applied with large variability (2.4.4).
• Drug substances: matrixing is of limited use and bracketing generally not applicable (2.2).
• Both together: bracketing and matrixing rest on different principles, so using both needs careful scientific justification.

What the design holds

For each storage condition, a table with every batch, strength and container and its state at every time point (tested, not tested by matrixing, not tested by bracketing) and the number of tests; the pulls per time point with the samples, units and dates; the reduction achieved against the full design; the units to place per combination with the reserve; every check against Q1D with its outcome; a chart of the samples tested per time point; the method, the limits that apply and lines for preparation and QA review. The workbook has a sheet per table.

Evaluating the data later

Data from a reduced design are evaluated in the same way as data from a full design (Q1D 2.5): use ICH Q1E — for example the Shelf-Life Estimation tool — with the time points the design tested. Matrixing on factors other than time generally gives less precision and a shorter shelf life than the full design.

Limitations

• The design applies the method you choose; your QA approves the result. The page checks the structure of the design against ICH Q1D, not the supporting data that justify it.
• Up to 12 batches, 12 strengths and 12 container sizes or fills, and three storage conditions at a time.
• Strengths and packs are bracketed by their order as entered: list them lowest and smallest first, and show that the levels tested really are the extremes.
• Matrixing on factors uses the same reduction as matrixing on time points, as in Q1D Table 3b.
• Pull dates count calendar months from the study start; the pull window your procedure allows is not added.

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