Managing risks

An important component of QbD is a risk-management system able to identify and evaluate potential problems. The ICH Q9 standard describes various methods that manufacturers and regulators can use to establish quality risk-management (QRM) systems that determine the appropriate level of control for a manufacturing process. At a time when industry is under increased pressure for more transparency in R&D activities and for strict compliance with diverse regulations around the world, a more proactive and systematic approach to information disclosure and communication is vital, explained Hoffman-LaRoche Global Quality Manager Stephan Roenninger. QRM provides a systematic process for controlling product quality, which also may prevent overly restrictive and unnecessary requirements.

Why QRM? QRM involves identifying risks (things that might go wrong with a process or product), analyzing the risks (assessing the probability of something going wrong), evaluating the consequences of a high-risk event occurring, and establishing policies for risk reduction or acceptance. The aim is to identify the most essential areas to monitor and evaluate, as well as where such efforts may be unnecessary or redundant. An annex to the guidance describes more specifically how to apply risk management to documentation, product defects, inspections, change management, maintaining facilities and equipment, material management, and validation.

Risk-based regulation. For FDA, a risk-based approach is being applied to standards development, regulatory decisions, inspection choices, and setting enforcement priorities, Woodcock explained, noting that the need to target its limited resources to the highest-risk areas requires a broader understanding of risk-based control models for managing manufacturing issues. Famulare added that FDA is using risk management to select sites for GMP inspections as well as to audit adverse-event reporting and sampling programs. FDA asks "so what" and "what if" questions in evaluating a system and state of control, Famulare explained.

Not surprisingly, manufacturers fear that this heightened focus on risk management could generate new requirements and prompt operations expansion. Kaufman of Abbott voiced concerns that Q9 implementation could force companies to adopt certain risk-management approaches and collect excessive information. "We don't want a quality risk-management department in every corner," cautioned Malcolm Holmes, director for global quality assurance at GlaxoSmithKline, noting the recent proliferation of process-validation operations.

Regulatory authorities insist that the ICH documents do not impose new requirements on industry. But, they also acknowledge that they "strongly encourage" companies to adopt more advanced approaches for ensuring manufacturing quality and demonstrating process control, and increasingly will look for such programs in weighing a company's ability to meet standards and regulatory requirements. As Robert of the European Union quipped at the workshop, "Implementation of Q9 is optional, but quality risk-management is not."

Encouraging innovation

To implement quality manufacturing and risk-based approaches, industry must invest in new technology, including statistical process controls and continuous processing methods, added Woodcock. There is growing confidence that "we have the science and technology to get there," she commented, and now "we need to change the system."

EU regulators say they are committed to accepting and evaluating QbD-based applications, but continue to display some skepticism about these approaches. Several applications containing "PAT elements" are under review through the European Union's centralized process, Germany's Keitel reported, and others are in the pipeline. But, additional expertise may be needed to evaluate innovative methods, and case-by-case review may require new regulatory approaches.

FDA's efforts to encourage manufacturers to adopt QbD and risk-based approaches will be explored further at an FDA workshop in late February on its GMPs for the 21st Century initiative. The aim is to review what has been accomplished so far under this campaign to modernize FDA oversight of drug manufacturing, what new challenges have emerged in achieving initial goals, and what remaining issues must be addressed to continue moving forward.