FDA’s report on pharmaceutical quality for the 21st Century in 2004 put forth their vision for reorganization within the FDA that would strengthen their ability to ensure drug quality.

As part of FDA’s reinvention and modernization, they created the Office of Product Quality ‘to promote “One Quality Voice” through the integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality.’

Achieving this goal is a significant undertaking. It should provide consistency within the FDA and in their interactions with stakeholders — something all stakeholders can applaud, if it is implemented effectively.

To this end, FDA published a 9-page aspirational view of their One Quality Voice effort.

Page 5 includes an excellent graphic on the components of the team-based approach to quality assessments throughout the product life-cycle.

Here we address some of the prominent features in the white paper and some questions it raises.

Prominent Features

FDA begins by identifying 6 ‘Challenges to Pharmaceutical Quality’ that include:

“Failures in the implementation of manufacturing process scale-up as well as routine production.
Shortages…caused by the use of outdated equipment, reliance on aging facilities operating at maximum production capacity, and lack of effective quality management systems.
A burdensome regulatory framework [that] requires manufacturers to submit supplements as they strive for process optimization.
A disproportionate amount of regulatory attention is devoted to low-risk products and issues, diverting resources needed for the assessment of high-risk products.
FDA has only limited information about the current state of pharmaceutical quality. FDA…lacks resources to comprehensively review annual reports and other data.
Inspection is not well-connected to knowledge gained from product review.”

It seems that resolution to numbers 1 and 2 are ‘owned’ by the industry and resolution of numbers 3 – 6 are largely owned by FDA.

I find reason number 5 to be the most troubling and suggests a deeper problem that may be far more difficult to resolve.

Regarding Item 5

The industry currently provides a wealth of information to FDA in annual reports, recall information, Field Alert Reports, and Biological Product Deviation Reports.

That fact that the FDA states they do not have resources to review and make complete use of these data is troubling.

This staffing limitation calls into question whether the FDA has resources to review a firm’s submissions of Quality Metrics in various stages of development and pilot evaluation. Perhaps FDA needs to find a way to make use of information that is already available to them before requesting additional data from industry.

Also, FDA states that ‘inspection findings have not been a reliable predictor of the state of quality.’ That seems to suggest that a complete overhaul of the inspection program and process is necessary.

The New Inspection Protocol Project

FDA seems to be working toward this goal, but that is a long-term effort and won’t happen quickly. Nothing will suffice for experienced investigators, and turnover at FDA may make it difficult to retain institutional knowledge regardless of how many detailed inspection checklists they prepare.

OPQ Summary

The white paper provides an organization chart for OPQ + the 8 sub-offices and follows with a summary of the responsibility of each office.

Section 4 identifies the objectives of the Office of Pharmaceutical Quality which include:

“Assure that all human drugs meet the same quality standards to safeguard clinical performance;
Enhance science and risk-based regulatory approaches;
Transform product quality oversight from a qualitative to a quantitative and expertize-based assessment;
Provide seamless integration of review, inspection, surveillance, policy, and research across the product life cycle; and
Encourage development and adoption of emerging pharmaceutical technology”

Regarding item #1 above, FDA elaborates on this objective and discusses the need for and importance of a move toward clinically relevant specifications.

“Clinically relevant specifications increase flexibility within the pharmaceutical manufacturing sector while maintaining quality by establishing acceptance criteria based on clinical relevance, instead of process capability or manufacturing process control.”

This sentence is interesting because it appears to minimize the importance of process capability and manufacturing process control — a statement that is substantially at odds with recent warning letters that cite failures in process validation (particularly the failure to have ongoing monitoring of in-process controls).

Perhaps a better phrase would stress the importance of clinically relevant specifications and acceptance criteria in addition to process capability and manufacturing control. Knowledge of process capability and ongoing in-process manufacturing controls will ensure that products continually meet clinically meaningful acceptance criteria.

Section 4.3.1 addresses “Product Quality Platform and Informatics.” The goals of this effort are laudable and, when implemented, will permit FDA staff, reviewers, and investigators to have available comprehensive evaluations of the firms they regulate. Decision making will be more data-driven and risk-based. Everyone supports these goals. The devil, however, is in the details.

Achieving this goal seems to require far more advanced IT systems and analytical capability than FDA currently possesses. IT modernization has been an often-stated goal of the FDA, and realization of the previously stated goals seems to depend on a capability that the FDA has yet to realize.

We can only hope that congressional appropriations permit the time, effort, and necessary expertise to make this goal a reality and ensure its ongoing maintenance and improvement.

Section 4.5 addresses FDA’s encouragement of the “Development and Adoption of Emerging Technologies.” I look at this a bit differently. I see FDA’s responsibility to develop a regulatory oversight process that provides an environment where industry can adopt new technologies and refine existing technologies. All without undue regulatory burden and time delays where product quality and patient safety is ensured.

I don’t see it as FDA’s responsibility to advocate for implementation of specific technologies as they are doing now with continuous manufacturing.

What’s Next?

I ask that FDA provide a follow-up article(s) with detailed information on when they will implement the various aspects of this program and how they will measure success of the overall program.

This article identifies laudable aspirational goals. They surely will be a work accomplished over time, but it would be appropriate to communicate interim timelines and reports on ongoing activities. Goals such as these should be specific, measurable, achievable, time-bounded, and realistic (SMART) consistent with FDA’s current level of funding and personnel resources.

About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence. She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.

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