Industry, Regulators Move to Adopt Quality Standards

"Quality by design" (QbD) and "quality risk management" at long last seem to be moving from the buzzword stage to becoming important influences on drug development and manufacturing. A series of quality standards issued by the International Conference on Harmonization (ICH) is encouraging the adoption of common quality-based drug manufacturing approaches designed to reach the "desired state" of drug manufacturing (i.e., more efficient, agile, flexible operations that can reliably produce high-quality drug products with less regulatory oversight). These developments reflect increased pressure to make pharmaceutical manufacturing more efficient and less wasteful and to encourage regulators in all regions to focus on the most critical issues affecting product quality and patient safety.

Jill Wechsler

Out with the old. Pharmaceutical manufacturing has not been "state of the art," observed Janet Woodcock, deputy commissioner of the US Food and Drug Administration and prime mover behind the agency's manufacturing modernization campaign. At a December conference on implementing ICH Q8 and Q9 sponsored by the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral Drug Association (PDA), Woodcock described why drug manufacturing is running up costs as high as research and development (R&D) investments at many companies. Woodcock asserted that factory utilization rates often are a low 15% because of batch-production processes, waste may top 50% for some products, scale-up is unpredictable, global operations are fragmented, and manufacturers often don't know the reasons for production failures.

Under the traditional manufacturing model, companies have submitted extensive chemistry, manufacturing, and controls (CMC) data to FDA that set tight product specifications. The aim has been to establish a production process able to meet those specifications consistently. Process change is costly and may result in drug shortages, delays in new product development, and the need for more oversight than FDA can afford to provide.

Testing new approaches

Defining a design space. The new approach calls for manufacturers to use modern statistical and analytical methods to define the critical sources of variability in a production system and establish appropriate quality controls. Manufacturers that can demonstrate to regulatory authorities a sufficiently high level of understanding and control may benefit from a smoother application-approval process and reduced oversight through the product life cycle. Risk management can help companies identify activities that require closer monitoring and those that merit less attention.

Woodcock expressed optimism that industry is beginning to move toward this more efficient and science-based process. She envisions pharmaceutical manufacturing systems based on extensive company knowledge about critical production and process parameters that define a "design space." Instead of reviewing massive amounts of data, checking batches, and spending days inspecting facilities, FDA would shift its role to initially verify a quality production operation, followed by periodic audits of systems for ensuring product quality.

The bottom line for FDA is a big reduction in manufacturing supplements. Companies must now inform the agency when they make relatively minor changes in production processes and suppliers. The goal is to limit such filings to major changes (e.g., developing a new formulation) and end supplements for the vast number of modifications and improvements that occur within predefined parameters.

Seeking harmonization

The shift to such QbD approaches also provides an opportunity to move away from disparate regulatory requirements and put everyone "on the same page," Woodcock commented. To this end, ICH participants from the United States, Europe, and Japan have developed a series of guidances for establishing a more science-based approach to ensure the quality of products and processes.

The ICH Q8 guidance on product development has been adopted by the European Union, Japan, and the United States. An FDA guidance was published in May 2006. The Q9 guidance (issued in June 2006) on risk management has been adopted by Japan and the United States, but still awaits final implementation in Europe.

A third document (Q10), which is still under development, will link product development and risk management to assist manufacturers in establishing pharmaceutical quality systems. Such programs will include systems for monitoring process and product, for taking corrective actions, and for managing change in the postmarket environment.

The ultimate quality system begins with the development of active ingredients and excipients and moves through product formulation, manufacturing process development, design of container closure and packaging, product release, storage, and eventual distribution, explained Jean-Louis Robert, representing EU authorities at the ISPE–PDA workshop. Such an approach features systematic methods for information collection, storage, and dissemination through the product life cycle.

Many of the elements in this science-based, QbD approach are similar to policies and guidances developed under FDA's good manufacturing practice (GMP) modernization initiative, according to Karen Main of AstraZeneca. FDA issued a guidance to help manufacturers adopt process analytical technology (PAT) systems in September 2004. In fall 2006, the agency published a guidance designed to encourage industry to establish quality systems.

Extending Q8

The Q8 guidance explains how manufacturers should provide information on product development and quality manufacturing in the P.2. section of the ICH-developed Common Technical Document for new drugs and biologics. This section provides a place to present the product-development report traditionally included in European dossiers. Manufacturers in the United States have been reluctant to share extensive development information with regulators, but industry globalization makes a more harmonized approach important, Main noted.

Although Q8 started off fairly targeted, it expanded during the ICH guidance development process to describe more fully how a manufacturer can establish effective quality control and design systems. The resulting document describes the scope of QbD, the ways that starting materials and process parameters affect product quality, and how the process should be monitored, evaluated, and updated to ensure consistent quality over time. The key is to identify and control critical sources of variability to adopt appropriate control strategies.

An important concept is to establish a design space for the product, noted Susanne Keitel of Germany's Federal Institute for Drugs and Medical Devices. This multidimensional construct consists of process parameters and material attributes that can ensure desired product quality reliably and reflects in-depth product knowledge and process understanding. The positive response to the Q8 guidance is encouraging further expansion. An ICH working group is developing annexes on oral dosage forms and moving on to parenterals in the future.

Flexible oversight

Manufacturers that display a high level of understanding about how a product is vulnerable to change and how its system can detect and control the production process may gain approval more quickly and enjoy reduced oversight of manufacturing changes after a product comes to market. For example, working within the design space is not considered making a change in the product or process from the regulatory viewpoint, pointed out Moheb Nasr, director of the Office of New Drug Quality Assessment (ONDQA) in FDA's Center for Drug Evaluation and Research (CDER). This kind of regulatory flexibility may permit manufacturing-process improvements without further regulatory review and reductions in end-product release testing.

Formalizing flexibility. The full implementation of Q8 and QbD methods ultimately could lead to a more-formal regulatory agreement between a manufacturer and regulator about what kind of postapproval regulatory flexibility would result from the adoption of modern quality-systems approaches. If a manufacturer provides very specific information about how it controls a manufacturing process as part of its application, that could lead to some kind of "compliance commitment" from FDA, explains Nasr. The agency is inviting manufacturers to propose such regulatory agreements, and FDA officials and lawyers are discussing internally how such agreements could fit within the existing compliance system.

So far, FDA has not negotiated any formal agreements, but has been discussing generally how it could implement the concept and how such information would be shared with the public. As part of its CMC pilot-review program (see sidebar, "Testing new approaches"), applicants have requested regulatory flexibility, and ONDQA has agreed to certain regulatory modifications. These changes include replacing end-product testing with in-process testing of blend uniformity, and allowing postapproval changes within an established design space to be filed in an annual report.

Regulatory agreements would have to be negotiated separately for each product and dosage form, which admittedly would be a time-consuming process. Nasr expects that a manufacturer would submit a proposed agreement in an application for FDA to evaluate as part of the approval process. FDA would need to devise an agreement document enforceable under CMC review and compliance policies, and additional FDA guidance would be needed to implement such a policy.

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.

The value of Q9 is to provide a common language and process for implementing QRM and for understanding where such approaches can add value, pointed out CDER Office of Compliance Deputy Director Joe Famulare. Zena Kaufman, director of the Quality Center of Excellence at Abbott Laboratories, described her company's efforts to distill out the essential elements of Q9 for quality systems in its diverse business units. And, Johnson & Johnson executives explained how they are using QRM procedures to choose among equipment replacement options and decide where the company can modify environmental-monitoring sampling without compromising product quality or patient safety. QRM also helped develop a five-year plan for capital expenditures in facilities and equipment based on potential risk to safety, operations, and regulatory compliance.

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.