In November 2008, the US Food and Drug Administration issued Draft Guidance for Industry—Process Validation: General Principles and Practices (1). The guidance outlines regulatory expectations for process validation following a "life-cycle concept" that describes
a "cradle-to-grave" approach for validating pharmaceutical processes (2). The life-cycle approach builds upon the results
of experimental activities during development to define operating parameters and product specifications that are used in initial
and ongoing process qualification. The life-cycle concept provides a robust means for the development, manufacture, and control
of pharmaceutical products.
The guidance document covers validation largely at a conceptual level and avoids narrow precepts and specific examples. This
approach is appropriate because the document addresses the subject from active pharmaceutical ingredient (API) production
(by either chemical synthesis or biological processes) through drug-product production for all pharmaceutical dosage forms.
The intended breadth of coverage embraces a myriad of unit operations in the preparation and manufacture of these products.
Unstated is whether the draft guidance is intended to be applied to supportive processes that are not an inherent part of
the formulation process. Among the support processes are cleaning, inspection, sterilization, and aseptic processing. Each
of these processes can be an essential part of pharmaceutical manufacture that requires validation.
Basics of the draft guidance
The draft guidance recommends a defined and structured approach for process-validation activities within an organization.
During the design and development stage, experiments should define the relationship between the independent process parameters
and the dependent product attributes. These studies should be conducted in a predefined manner, and the results should be
documented for later reference. The goal of process development is the attainment of knowledge regarding the process–product
relationships to support later commercial production. The greater the knowledge accumulated at this early period, the more
assurance the firm will have that it can successfully launch and maintain the process at a commercial scale. From a compliance
perspective, this approach makes excellent sense; the knowledge gained during preclinical and clinical-stage experimentation
provides a way to link clinical data obtained at the smaller scales with data from the later production process. A well-developed
process is one for which the critical process parameters have been identified and control ranges for each have been established
(3). The development experiments should evaluate the interaction between the independent and dependent variables until the
results of the process are predictable and routinely acceptable. Multifactorial experiments can assess the relationships between
the variables and build knowledge about the process's limitations. The experiments performed at a smaller scale establish
the acceptable ranges for the various independent process parameters. Thus, when the process is operated under the appropriate
conditions, operators have substantially greater confidence that the desired quality attributes of the product will be realized.
The acceptability of the end result is ascertained using samples of the completed materials.
Initial and ongoing qualification of production processes are the means for establishing and confirming the experimental experience
at significantly larger scales of operation. Knowledge gleaned from the development simplifies later activities. Production
processes are always operated within the defined operating ranges because there is no reason to experiment with conditions
at the extreme ends of the ranges on this larger scale. Challenges during these stages are primarily in the number of tests
performed on the produced materials. Qualification lots are customarily sampled at a substantially higher rate than are routine
production lots, and testing of these expanded samples is the challenge of the commercial process. The guidance recommends
using appropriate statistical tools in the full-scale qualification efforts to provide the desired confidence in process and
product acceptability and thus attain the desired validated state. The expectations for statistical evidence in process validation
are well founded; sampling batches at the modest levels associated with pharmacopeial tests provide little, if any, proof
of end-product quality. Although those tests may be legally binding, they have only limited value. Industry has largely ignored
the levels of "real quality" needed to support its claims for patient welfare (4).