Real-world examples
Approaches to bracketing in process validation
|
Based on the clear support that equivalence seems to have, whether explicit or implicit, one might assume that the concept
is in widespread use. Regrettably, industry seems to be reluctant to use it to design validation programs. When industry uses
equivalence, little public information about its application and utility is available. This article draws extensively on the
author's experience because of the paucity of published information about applying equivalence to the execution of validation
studies. The following list of projects used the equivalent performance of multiple pieces of identical equipment to reduce
the overall validation effort.
Nine identical ovens.
One company used nine ovens to depyrogenate vials of 14 sizes. If equivalence were ignored, the number of studies required
to fully validate minimum and maximum loads would be 756 runs (9 × 14 × 3 × 2). Equivalence and bracketing (see sidebar, "Approaches
to bracketing in process validation") reduced the number of runs to 126 (9 × 2 × 3 + 12 × 2 × 3). The entire effort comprised
the largest and smallest vials in all ovens in both load sizes, plus single-minimum and maximum load-size runs of the other
12 vials in one or more of the other ovens. Equivalence reduced the workload by 83%.*
Paired terminal sterilizers.
A company planned to use identical units to sterilize 15 vial sizes filled with 32 formulations. A total of 56 possible product–container
combinations needed to be validated. The validation was expected to cover minimum, maximum, and intermediate-sized loads.
Without equivalence, the number of required validation runs to be completed would be 1008 (2 × 56 × 3 × 3). Extensive sterilizer-qualification,
cycle-development, and water-challenge (covering five different vial sizes) runs were used to demonstrate the sterilizers'
equivalence and to support load-size variation across the breadth of containers. The initial product validation of the sterilizers
consisted of 54 biochallenge runs selected to broadly confirm the acceptability of the process for several of the formulations.
None of the product loads were tested in triplicate. These data and those from the water-challenge runs, in conjunction with
D-value determinations, was used to obtain initial facility approval. This information was supplemented postapproval with physical
monitoring that reaffirmed the physical parameters for the remaining products, containers, and load sizes. The overall reduction
in workload achieved through the use of equivalence was approximately 95%.
Other examples.
In addition to the applications described above, the author has participated in the following validation projects in which
equivalence reduced the overall effort:
- Terminal sterilization
- Part sterilization
- Clean- and steam-in-place of fixed and portable tanks
- Vial and stopper washers
- Tablet presses
- Coating pans and columns
- Granulation vessels
- Shelf, fluid-bed, and freeze dryers
- Compounding of oral and injectable solutions
- Mills and sieves
- Blenders
- Filling, packaging, labeling, and inspection equipment.
The abovementioned items represent the author's experiences and are not intended to be all-inclusive. One might reasonably
expect to demonstrate equivalence for other items of equipment not indicated above. The increased use of automated monitoring
and control in contemporary equipment makes it easier to demonstrate equivalence.
|
