By: Philippe Cini, PhD; Gretchen Allison; Gerald Leister; Eda Ross Montgomery, PhD; Julia O’Neill; Paul Stojanovski; Michael Thomas; and Arne Zilian, PhD
The response section maturity model is intended to identify events that trigger a response, the consistency of the response when those events occur, how well events and responses are aligned across products and sites, and the extent to which leading indicators and/or combinations of events are used to evaluate whether an event has occurred. An "event" is defined as an abnormal shift, trend, or low Cpk.
Maturity of the response portion can mean responding to failures, responding to both favorable and unfavorable changes in process capability, or responding to indications of a potential event based on leading indicators (e.g., comparing the predicted failure rate to actual failures). Maturity is also affected by the degree to which the effectiveness of the action is verified (e.g., ad hoc or no effectiveness check for a single event for a single critical quality attribute (CQA), or measuring effectiveness checks for all sites and all relevant products based on a specific event).
A robust response results in action based on established process or product thresholds, with resources and improvement activities for products with poor process capability. This consistent, focused response results in continuously improving process capability.
Survey responses for current-state maturity averaged 3.5 (defined-managed). Respondents reported that Cpk or Ppk are routinely calculated for CQAs and some other parameters such as process parameters or raw material attributes; this practice is not in place at all sites, however. At this level, the parameters, attributes, and/or CQAs where process capability is measured can also vary. Sites with response systems at this maturity level show a measurable influence on process capability. According to one survey respondent, "If Cpk < 1.33, it is discussed. Cross-functional team to understand ‘why’ are formed and plans are developed. Heads of quality or technical services will weigh in on Cpk < 1.0 … 95%–98% of Cpk are > 1.3."
Average future-state response maturity was 4.7 (managed-optimizing), indicating that companies believed that significant benefits would result from efforts to set consistent standards, respond to process-capability signals, report progress, and measure effectiveness across products and sites. More extensive and effective use of leading indicators with comparison to actual results was also desired. "Being able to predict problems before they occur results in significant business benefit," explained one respondent.
Survey participants rated themselves an average of 3.3 at current state, indicating that respondents found that their respective organizational structures suitably designed and staffed to collect, compile, and analyze process-capability information and signals; make recommendations; and take timely action. Roles and responsibilities are clear, associates experienced in determining process capability, and expert statistical support are readily available. Process capability programs have been in place for 3–15 years on average, an indication of the time typically required to achieve this level of organizational proficiency.
When asked to describe their future state organization and skills, the average response was 4.4. To achieve this level of maturity, process-capability activities must be well-defined for key business processes (e.g., technology transfer, CPV). Process capability knowledge must be pervasive and integral. Importantly, management fully embraces process capability to drive process robustness improvements and create value for the organization.
Comments indicated that as SOPs and organizations are created and training is provided, a culture change begins in which process capability becomes a standard approach to conducting business. Comments also emphasized the need for management support.
A risked-based (e.g., ICH Q9) approach to process capability prioritizes and applies resources where they are needed most to enhance patient safety, guarantee compliance, ensure efficient use of resources, and drive business value.
Participants rated themselves an average of 3.3 at current state. This means process-capability approaches, policies and SOPs are risked-based, in place, and mostly in use across the organization. Risk-management tools are also in use and are well defined. These approaches strengthen the organization’s compliance record and align with the FDA’s "Pharmaceutical cGMPs for the 21st Century, A Risk-Based Approach."
When asked where they would like their program to be in 2–3 years the average response was 4.2. To achieve this level, use of risked-based context must be applied consistently across the entire organization; increased proficiency in the use of risk-based approaches should also be demonstrated. Process capability monitoring must be aligned with the risk of processes performance. Business value is derived from the use of process capabilities at this maturity level.
Comments from respondents indicate that the use of process capabilities often start with a set frequency. As process-capability programs mature, the higher the risk, the more frequent the monitoring. Comments also indicate that risk analysis is used to prioritize processes to be improved upon, and can include more than just capability data.
Prior to process validation, scientific evidence must establish that the process is capable of consistently delivering quality product. The commercial process control strategy is defined in Stage 1, process design, and based on knowledge gained during development activities. Development data collection and evaluation is focused on process understanding, often including data from operating the process at extreme ranges to determine the relationship between operating parameters and quality attributes. Calculating process-capability indices at this stage may provide limited benefit because of the forced variation. In addition, at this stage of development, few runs at normal operating conditions have typically been completed (< 10). This can lead to considerable uncertainty in the process-capability estimate.
Evaluation of the process control strategy occurs during Stage 2, process qualification/validation. As appropriate and with proper scientific oversight, Stage 1 and 2 data may be combined to assess process capability. In Stage 3, continued process verification, a product- and process-performance program—including process-capability indices—can provide assurance that the process remains in a state of control and identify opportunities for continuous improvement.
Survey participants rated their current state an average of 2.6. This indicates that while the control strategy is sufficiently robust for validation purposes, the commercialization site may need to allocate resources to mitigate the risk of variability not apparent during development. Participants rated their future state at 4.0, on average. This indicates a desire to further optimize the control strategy during development and possibly find ways to enhance the use of process-capability indices at that stage of the product life cycle. Both averages (current and future) are the lowest observed in the survey. This is not unexpected as the commercialization area is the highest level on the process-capability pyramid (Figure 1).