The new guidance
The new guidance ushers in a life-cycle approach to validation. This approach is most apparent in the guidance's new definition
for process validation: "...the collection and evaluation of data, from the process design through commercial production,
which establishes scientific evidence that a process is capable of consistently delivering quality products" (1)
The words used have been selected carefully. The new definition talks about establishing process capability using scientific
evidence while previous definitions used the phrase "documented evidence" (4). This earlier definition may have contributed
to validation being viewed largely as a late-stage documentation exercise. The new definition, however, describes process
validation as a continuous process of collection and evaluation of data, rather than as a three-batch static event. As one
FDA representative commented at a recent PDA workshop, the number of batches is not an acceptance criteria; however, the results
of the data obtained from the batches are (5). The new definition of validation caused one industry member to lament at the
workshop that for the past 30 years, industry has been told that process validation is a documentation exercise. Now, FDA
expects industry to consider process validation as a scientific endeavor. That is quite a shift and 30-year habits are hard
to break, he noted (5).
This statement underlies the dichotomy that exists within the industry regarding the new guidance. For years, the industry
criticized regulators that the industry owned the expertise, knew their processes better than regulatory agencies, and should
have flexibility in how they could validate these processes. The agency listened and came back with a guidance that is deliberately
non-prescriptive; it doesn't tell industry how many samples to pull or how many batches to run. The industry has to be able
to answer these questions and they are not always easy to answer.
Defining the new process-validation stages
As noted, the 2011 guidance enforces the life-cycle model described in ICH Q10 and in FDA's 2006 guidance for industry on
Quality Systems Approach to Pharmaceutical CGMP Regulations, which states that, "quality should be built into the product, and testing alone cannot be relied on to ensure product quality"
(6, 7). The method of building quality into a product or "designing for assurance" challenges manufacturers to better:
- Understand the sources of variation along the supply chain in the manufacturing process
- Detect the existence and amount of variation that is imparted into the product from sources within the supply chain, the equipment,
- Understand the impact of the detected variation on the finished product
- Control the variation detected based upon the understanding and knowledge of the sources of the variation that proportional
to its risk to product and patient (1).
The new guidance document describes validation activities in three stages using a life-cycle model (see Figure 1). Although
explained as discrete stages, some activities can occur in multiple stages while others may overlap between stages. Risk assessments
are a good example of such activities. The guidance describes these three stages as follows (see Figure 1):
- Stage 1–Process Design: The commercial-manufacturing process is defined during this stage based on knowledge gained through
development and scaleup activities.
- Stage 2–Process Qualification: During this stage, the process design is evaluated to determine whether the process is capable
of reproducible commercial manufacturing.
- Stage 3–Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in
a state of control (1).
These stages are defined in more detail in the following sections.
Figure 1: The three stages of the validation life-cycle model based on the new FDA process validation guidance. (Authors)