With the most recent ICH and FDA guidances endorsing a new paradigm of process validation based more on process understanding and control of parameters and less on product testing, the means of determining criticality has come under greater scrutiny. The FDA guidance points to a lifecycle approach to process validation (see Figure 1). “With a lifecycle approach to process validation that employs risk-based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful.” The problem is that a practical approach of determining this criticality “continuum” using risk analysis has been left to each company to develop.
This article presents the first part of a practical roadmap that applies scientific knowledge, risk analysis, experimental data, and process monitoring throughout the three phases of the process validation lifecycle to first determine and then refine criticality. In this approach, criticality is used as a risk-based tool to drive control strategies (Stage 1), qualification protocols (Stage 2), and continued process verification (Stage 3). Overall, a clear roadmap for defining, supporting and evolving the criticality of parameters and attributes throughout the process-validation lifecycle will allow pharmaceutical companies to easily embrace the new process-validation paradigm. Furthermore, processes will be more robust and continuous improvement opportunities more easily identified.
In Part I of this series, the author used risk analysis and applied the continuum of criticality to quality attributes during the process-design stage of process validation. After using process knowledge to relate the attributes to each process unit operation, the inputs and outputs of each unit operation were defined to determine process parameters and in-process controls. An initial risk assessment was then completed to determine a preliminary continuum of criticality for process parameters.
In Part II, the preliminary risk levels of process parameters provided the basis of characterization studies based on design of experiments (DOE). Data from these studies were used to confirm the continuum of criticality for process parameters.
In Part III, the control strategy for the process was developed from a design space established from characterization studies. As the process-qualification stage proceeds, the continuum of criticality was used to develop equipment qualification criteria and strategies for process performance qualification. Finally, in the continued-process-verification stage of process validation, criticality was used to determine the frequency of monitoring and analysis.
From binary to continuum
On the surface, deciding whether an attribute or parameter is critical or not may seem clear and simple. After all, data are compared to acceptance criteria in countless decisions regarding clinical trials, experimental studies, qualifications, and product release. Either the acceptance criteria are met, or they are not. Companies that take this familiar path have tried to draw a definitive line between the “critical” and “not critical” sides. Once a decision has been made about criticality, there is no need to look again. It doesn’t help that the guidance documents for industry have been vague on where this criticality threshold lies. The FDA’s PV guidance avoids the issue: “attribute(s) … and parameter(s) … are not categorized with respect to criticality in this guidance” (1).
ICH Q8(R2) provides the following definitions using the term critical:
• Critical process parameter (CPP). A process parameter whose variability has an impact on a critical quality attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.
• Critical quality attribute (CQA). A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
This interpretation of CQA is most applicable to in-process and finished-product specification limits, which suggests that these limits must be critical given that they were designed to ensure product quality. During the early stages of process development and design, other quality attributes may be measured that, over the course of development, do not end up as either in-process or finished-product tests in the commercial process. These test results may show little variation and present little to no risk to product quality. In other cases, while process duration or yield is measured, they are not related to the product quality and are, therefore, not CQAs. However, even when defined as critical, not all CQAs have equal impact on safety and effectiveness (3, 5).
The definition for CPP states that a parameter is considered critical when its variability has an impact on a CQA. The amount of impact is not defined, which leads to the question, does even a small impact to a CQA mean that the parameter is critical? It is not difficult to imagine the example of an extreme shift of a process parameter having a minor impact on a CQA, whether measurable or not. Extreme temperatures can destroy many pharmaceutical products; however, if a process inherently cannot produce such temperatures, is temperature still considered to be critical and, therefore, required to be monitored and controlled?
When these definitions are strictly interpreted, some companies find themselves in one of two extremes:
• Every quality attribute is critical (they all ensure product quality); every parameter is critical (product cannot be made without controlling them)
• No parameter is critical because if they are controlled, all quality attributes will pass specifications.
Reality lies somewhere between these extremes. Logic and common sense dictate that additional criteria must be necessary to aid in determining criticality. There is great value in understanding not only if a parameter/attribute is critical (i.e., has an impact), but also how much impact the parameter/attribute has. All companies have limited time and resources; therefore, the focus must be on that which provides the greatest benefit for the effort
By using risk analysis as a means to determine criticality, an opportunity arises to help resolve these potential conflicts. CQAs should be classified based on the potential risks to the patient. CPPs should be separated into those that have substantial impact on the CQAs and those with minor or no impact. The binary yes/no decision transforms into a continuum of criticality ranging from high impact to low impact critical to not critical. As knowledge increases or as improvements are made to a process throughout the lifecycle, risks may be reduced and the level of impact for a CPP can be modified and control strategies adjusted accordingly
The number of levels in the continuum is a matter of choice and the risk analysis method used. Each company must procedurally define what risk tools and risk levels it will use and consistently apply them across similar products. In the following examples, three levels of impact are used for simplicity’s sake. The different levels drive decision-making and action plans throughout the lifecycle.
For CQAs, a continuum of criticality provides a tool to designate particular attributes as the most important to the protection of the patient. For CPPs, a continuum of criticality allows for process control and monitoring strategies to focus where the greatest impact on product quality is achieved.