The FDA’s Groundbreaking Strides Toward a Quality-Centric Regulatory System

Two famous pharmaceutical industry quotes encapsulate industry thinking and the push for progress in recent years. Upon launching Pharmaceutical cGMPs for the 21st Century – a Risk-Based Approach, Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER), shared the following vision: “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight.”

Gerry Migliaccio, former head of global quality at Pfizer, once notoriously stated, “We produce six sigma products with three sigma processes.” Gerry was referring to the fact that the pharmaceutical industry’s over-reliance on compliance-based inspection to achieve quality is a very ineffective way to do business and that most other industries, even those in heavily regulated environments such as nuclear and aviation, moved away from this way of working many years ago.

Before exploring FDA action to achieve the outlined vision and address the great challenge shared by Mr. Migliaccio, it is important to recognize some of the primary pharmaceutical quality issues the industry and regulatory community have been wrestling with in recent years:

• Treatment of all products equally, resulting in a disproportionate amount of regulatory attention devoted to low-risk products, diverting needed resources for high-risk products.
• Unacceptably high levels of product recall and defect reporting that is too frequently rooted in defects in product and process design.
• Shortages of critical drugs in recent years are also often the result of ineffective product and process design and the lack of effective quality management systems.
• Inspections are not well connected to knowledge gained from product review and applications.
• Because current FDA practice “locks in” a process before it is fully optimized, post-approval supplement submission levels are substantially higher and are a burden to both the FDA and industry.
• Product review is often conducted based on pre-marketing data from exhibit or clinical batches. There may be significant differences between these data and the conditions of commercial production.

So, within an environment of increased drug product complexity, the need for greater numbers of different specialty drugs to treat smaller patient populations, and more complex drug product supply chains, the industry and the regulatory community still:

• Do not understand their products and processes to the degree necessary
• Are hampered by a compliance-based regulatory framework that does not allow easy adjustment of processes based on the ongoing accumulation of product and process understanding
• Operate within the framework of all products, regardless of risk, essentially being treated equally

To move toward a system that ultimately regulates quality rather than compliance, the FDA and other regulatory bodies around the world are working to move to a system that considers drug product risk in a strategic manner. As other heavily regulated industries have already recognized, all products and situations should not be treated equally. Rather, regulatory resources need to be more heavily focused on the greatest areas of risk.

To achieve a risk-based construct, CDER’s new Office of Pharmaceutical Quality (OPQ) formulated the New Inspection Protocol Project (NIPP) incorporating five priorities: regulatory science, globalization, safety and quality, smart regulation, and stewardship.

NIPP will strive to differ from regulatory and inspection practices that have been in place for decades by using informatics, internal analysis, and other digital tools to prepare for and steer inspections. By utilizing data and predictive analytics, NIPP will allow the development of algorithms to reveal product quality challenges and facilitate inspections that concentrate on high-risk, inconsistent processes and products. A key aim of the NIPP is to focus attention and resources on high-risk processes and products so that, ultimately, quality improvements can be identified and made more quickly.

Organizationally, the NIPP consists of three subgroups: Pre-approval Inspection Protocol(s) subgroup, the Surveillance Inspection Protocol(s) subgroup, and the For Cause Inspection Protocol(s) subgroup. These subgroups will mine regulatory data to improve the FDA’s understanding of processes and approaches that produce quality products.

The FDA is using informatics as the cornerstone of NIPP. A database will evaluate the history of a given pharmaceutical manufacturing site for the following eight facility risk factors:

1. Process
2. Research
3. Analytical Methods
4. Sterility/Microbiology
5. Inspections
6. APIs and Excipients
7. Chemistry Manufacturing and Controls (CMC), and
8. Policy/Enforcement Actions

An algorithm will calculate the findings from the historical data and integrate them with product and facility risk factors to calculate a site ranking. Ultimately, higher-risk pharmaceutical manufacturing inspection sites will be identified and given priority resources.

To increase regulatory efficiency, based on the knowledge garnered from the NIPP inspections, the FDA can make more informed decisions on frequency of inspections, prioritization of inspections, and more effective pre-inspection planning so that time on site is optimized as fully as possible and hours are reduced as much as possible.

In the end, NIPP’s and OPQ’s goals are to strive for inspections that determine quality and more closely scrutinize risk-intensive products and operations, rather than inspecting for adherence to SOPs and other such regulatory criteria that may or may not lead to higher-quality products that reduce patient risk.

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