CLEANING METHOD QUALIFICATION
The same approach can be taken for cleaning equipment and components (e.g., resins, membranes) that is taken with cleaning
of areas in the facility (i.e., floors, walls, ceilings). The cleaning agents used should be assessed for both compatibility
and effectiveness. To assess compatibility, studies to show that the cleaning method do not adversely affect the contact surfaces
should be performed.4,8,9 To evaluate cleaning effectiveness, the cleaning method should be challenged with various types of organisms (e.g., gram-negative,
gram-positive, yeast, spore former,)—preferably environmental isolates—to show the objective of cleaning is met. Because it
is practical to perform cleaning validation during the process validation batches, it is important to ensure that all cleaning
methods are appropriate for use and qualified to appropriate limits.
STAGES OF PROCESS VALIDATION
The three stages of process validation are shown in Figure 2. Stage 1 comprises pre-qualification activities used to generate
the list of critical process parameters used in the manufacturing qualification protocol. Stage 2 is the execution of the
manufacturing qualification and stage 3 is ongoing process monitoring through life-cycle qualification.
Figure 2. Three stages of process validation
Stage 1 entails performing process understanding studies to establish the design space for all process parameters, determining
which parameters are critical, and executing supporting validation studies. Because the pre-qualification activities involve
the evaluation of process parameters and their ranges, they will not be meaningful until the manufacturing instructions are
finalized. The key to meaningful pre-qualification studies is a process pre-qualification plan that is based on a well-defined
manufacturing process. This is completed by a thorough analysis of the potential study and how it relates to the desired quality
attributes in the finalized process. For example, chromatography resin re-use (lifetime) studies should only begin when the
complete chromatography cycle (sanitization, equilibration, loading, elution, regeneration, cleaning, and storage) and the
procedure for the manufacture of the starting material (i.e., load) are defined.
The parameter risk assessment and range-finding studies should only begin when a complete list of parameter ranges from the
manufacturing instructions is compiled. Therefore, the final manufacturing instructions must be in place for the assessment
to be meaningful. Each parameter is assessed for its potential to affect (positively or negatively) the applicable process
controls or quality attributes. Each parameter is given a numerical rating based on the likelihood and potential magnitude
of impact (e.g., failure modes and effects analysis, FMEA), which often includes an evaluation based on scientific rationale
of the control mechanism.1,10 The parameters that have the highest likelihood and potential to affect the process are entered into range-finding studies
(e.g., DOE, OFAT) and the outcome for each studied parameter is the relationship between its normal operating range (control
space) and its proven acceptable range (design space).11,12 The normal operating range is the range at which the parameter is typically controlled during routine operations and is
usually the range found in the manufacturing instructions. It takes into account the minimum and maximum values tested during
initial development and a review of process history, which shows the capability of the operators, facility, equipment, and
utilities. The proven acceptable range is defined by the minimum and maximum values for each parameter found during the range-finding
studies. Range-finding studies are often designed such that the ranges studied are 2x or 3x the normal operating range.