The keys to equivalence
Central to the use of equivalence is the establishment of criteria for the evaluation of the equipment's operational performance.
This evaluation demonstrates that individual units perform identically. Criteria must be chosen with some restraint; adding
too many criteria or nonessential criteria is unlikely to add meaningful value and more likely to result in the conclusion
that the equipment is not equivalent. Common sense indicates that the criteria should focus on the crucial aspects of the
equipment's performance. For sterilization processes, that most important criterion would customarily be F
0.* Other criteria in this determination for a sterilization process would add no meaningful value because these processes
are intended to achieve lethal conditions. Criteria for other processes could be defined by their key performance measures
(e.g., content uniformity, potency, fill weight, and residue level). Another possibility is to use a defined and calibrated
test set as a standard for assessment. Test sets are ideally suited for attribute, foreign-particle, and label-inspection
equipment and systems.
Regardless of what criteria are chosen, it is appropriate to establish in advance an acceptable range for equipment performance.
In setting this range, one should consider the following factors:
- The inherent analytical variability or measurement sensitivity used to assess the results
- The normal variation in the underlying process
- The limitations of sampling.
These factors should be first evaluated on a single piece of equipment in replicate studies in which these and other factors
are assessed for their influence on the results. A single piece of equipment tested in replicate studies during a brief interval
must be considered equivalent to itself. The actual variations between multiple items should be somewhat, but not dramatically,
larger. In the absence of an independent assessment, the author suggests a range of not more than ±10% of the target value,
which itself is an average of multiple preliminary runs.
Should the firm set overly restrictive criteria or the equipment prove not to be equivalent, nothing is lost. The accumulated
data must be augmented with whatever added studies are necessary to complete the overall exercise without relying on the simplifying
effect that equivalence can afford.
An aspect of equivalence that has largely been ignored is that of time. It is essential that any process provide consistent
results over time, whether the process is performed with a set of equivalent equipment or in a single piece of process equipment.
This principle might seem obvious, but FDA codified that expectation in the draft revision of the Guideline on General Principles of Process Validation (1). The expectation that a firm can establish equivalence across multiple items at a single point in time is wholly appropriate
for the same firm using a comparable approach to demonstrate the equivalence of the same piece of equipment over several points
in time. This is a core expectation of the revised guidance and should raise awareness of equivalence as a regulatory expectation
when FDA finalizes that document.