The criticality of each process parameter is determined by analyzing the relationship among the operating range, acceptable
range, and the failure limits. In general, if the acceptable range is more than 2x the operating range (Figure 3a), then the
parameter is considered non-critical.12 This suggests that the parameter can be controlled tightly by the operator or automation system, and even a significant
deviation from the set point would not affect the manufacturing process. Conversely, if a parameter's operating range is less
than 2x its acceptable range (Figure 3b), this indicates that a deviation to the normal operating range would likely result
in a failure to meet an in-process control, in-process specification, or failure of the batch. This parameter would be deemed
critical. This analysis is continued until the criticality of all parameters is evaluated, and their actual impact on the
process has been determined.
Figure 3. The differences between noncritical and critical parameters.
Stage 1 is also the stage in which supporting validations are performed. In some circumstances, not all supporting validation
studies are completed before stage 2; however, these studies still fall in the category of process pre-qualification. For
example, during shipping validation studies, the packaging and shipping processes are defined, qualified and validated. These
studies could be performed after stage 2 and use the shipments of the material produced during the manufacturing process qualification
to confirm shipping conditions. In this example, the packing configuration, procedures, laboratory simulations and study design
would be completed in stage 1, but the actual shipment verification would be performed after stage 2 is complete.
Stage 2 entails the performance of three consecutive runs at the intended commercial scale.13 The manufacturing process qualification is performed under a prospective protocol using the appropriate output and results
from the stage 1 studies (i.e., critical parameters), in-process controls and specifications, and any additional criteria
specific to the process.
Stage 3 is the ongoing assessment of process performance through life cycle qualification and management of process changes.14 Criteria are outlined in a prospective life-cycle qualification protocol and appropriate standard statistical process control
(SPC) techniques (control charts, ANOVA, Western Electric Tests, etc.) are used to confirm ongoing acceptability of process
performance.15 Critical process parameters are monitored routinely during batch release and compiled with the SPC data for annual reporting.
After validation, all changes made to manufacturing procedures are assessed for impact to the validated process, and revalidation
is performed as needed.
Developing a process validation strategy early in clinical development is critical to the execution of a successful validation
program because process validation is more than just running three consecutive batches under protocol. The magnitude of activities
leading to the qualification batches requires resources and expertise that far exceed those in place for routine development
and production. However, if a sound strategy is developed for process definition and completion of the commercial batch at
an early stage, the risk of repeating the validation exercise is greatly reduced. With the proper resources put in place to
execute the comprehensive strategy, there is the additional benefit of generating complete and thorough lists of documents,
reports, flow diagrams, and other references that will facilitate regulatory submission writing, pre-approval inspection
readiness activities, and can be used to support the pre-approval inspection.
David M. Fetterolf is the associate director of manufacturing at BioTechLogic, Inc., Glenview, IL, 919.854.0785, email@example.com
1. International Conference on Harmonization (ICH). Q9, Quality risk management. Geneva, Switzerland; 2005.
2. Haider SI. Pharmaceutical master validation plan: the ultimate guide to FDA, GMP, and GLP compliance. New York: Saint
Lucie Press; 2002.
3. Lydersen BK, D'Elia NA, Nelson KL. Bioprocess engineering: systems, equipment and facilities. New York: Wiley-Interscience;
4. The American Society of Mechanical Engineers. ASME BPE-2002: Bioprocessing Equipment, An American National Standard; 2002