CDER Looks to Make its Own 'Case for Quality' for Drugs, Arguing it’s Good for Business and Consumers

Pharmaceutical manufacturers should be focused not so much on compliance, but rather on consistent quality operations as a means to drive sustainable compliance, officials from the US Food and Drug Administration (FDA) told attendees of the 2013 RAPS Regulatory Convergence conference in Boston last week.

Background

FDA has been exhibiting an increased agency-wide focus on quality in recent years, with a particular emphasis on medical devices. In its widely publicized "Case for Quality" initiative, FDA has been making the case that by building quality into its processes and the end product, companies can be more compliant with FDA's regulations while suffering fewer problems (and thus costs) in the long run.

It is, in other words, a shift from the reactive (snapshot compliance) to the proactive (quality-focused operations).

But to listen to FDA's drug regulatory officials at 2013 RAPS, it's not just device manufacturers who need to be thinking about the quality of their operations.

In one session-previously covered in Focus-Howard Sklamberg, director of the Center for Drug Evaluation and Research's (CDER) Office of Compliance, said there was a definite shift ongoing within CDER toward quality.

"CDER is focusing on ways of improving its assessment of quality," Sklamberg said. "We're in the process of forming an Office of Pharmaceutical Quality (OPQ)," which would combine many review functions--good manufacturing practices and chemistry, manufacturing and controls, for example--that are currently spread throughout various CDER offices into one office.

The goal, Skalmberg said, is to adopt a "lifecycle approach to reviewing products," much in the same way that regulators within industry often work.

Quality and Business

Those remarks were complemented in a later session attended by Richard Friedman, associate director of the Office of Manufacturing and Product Quality, also within the Office of Compliance.

Friedman said the most important thing to keep in mind about maintaining good manufacturing practices is consistency. And in the pharmaceutical sector, this consistency can sometimes take a back seat to revenue and margin pressures, he said, citing a survey that said most companies are willing to sacrifice long-term economic value in order to deliver short-term earnings growth.

Friedman recounted one instance in which a company had skipped out on some quality improvements during a fiscally tighter time period, believing it would be of little consequence. A subsequent quality-related problem led to significant problems in the long run, costing the company far more than it would have spent had it identified the problem when it would have under the existing quality inspection regime.

"Quality-oriented leaders establish systems that detect problems," he said, giving them early indications of problems through a focus on processes that might be leading to out-of-trend results that aren't necessarily out-of-specification.

Making Improvements

"We must ask ourselves, in an area where the stakes are so high, why are [high degrees of quality] not being achieved?" asked Friedman, referring to an article in which his boss, CDER Director Janet Woodcock, questioned why the pharmaceutical industry had not met the same six-sigma quality management techniques exhibited in many other manufacturing sectors.

Friedman argued industry could make substantial improvements to compliance and production if it only focused on issues related to quality in a proactive way, and listed seven things that a "robust quality system" includes:

• It must have a science-based foundation.
• The quality system must be at the core of the GMP framework of the company.
• It must be vigilant and proactive.
• It must be able to identify potential problems and address them while they are still minor in size, scope and effect.
• Any contracted operations must also adhere to the same quality standards.
• There must be a culture of quality promoted within a company for it to work.
• It should support business needs through dependability and sustainability.

The take-away, Friedman said, is that risk isn't something that should just happen-it's something that needs to be mitigated through proper management.

Common Deficiencies

Friedman said his investigators often find 12 common deficiencies at manufacturing facilities, generally related to poor quality risk management principles:

1. Standard operating procedures aren't followed.
2. Tests are repeated on out-of-specification products until compliance-not quality-is met.
3. Complaints aren't properly investigated.
4. Trends aren't detected or investigated.
5. Investigations fail to detect if an issue is isolated or recurring (e.g. root cause analysis).
6. Investigators lack the experience necessary to determine where problems are occurring or how to correct them.
7. Contract manufacturing partners are improperly managed.
8. Stability failures are improperly handled.
9. Root cause is not established or the problems are not corrected.
10. Effectiveness is not checked.
11. Patchwork corrections are made, leading to ongoing issues when those fail.
12. The technology choice used at launch is ineffective or incapable of providing long-term quality manufacturing.

The shift that needs to happen, Friedman said, is one away from static compliance snapshots and more toward an assessment on a product's lifecycle. Future evaluations will seek to determine if the company exhibits a state of control over a product throughout its lifecycle, and to see if a facility is able to manage risks while allowing for technological advancements and improvements.

But to do this, the industry is going to have to get more closely involved, he said. Management within companies are going to have to enforce a culture of quality, even when it goes against what Wall Street is calling for in earnings reports.

Manufacturing Scorecards

And the success of that involvement may well be scored by FDA, Friedman confirmed in response to a question by Regulatory Focus.

We asked: Is the agency considering-as Woodcock has suggested-using and releasing manufacturing scorecards to help consumers assess the quality of pharmaceutical products?

"We are going to be doing, at least internally, quantitative assessments of product performance and quality performance. In terms of whether it will ever be public … that isn't the plan right now," he said, referring to a quality scorecard being published by the agency.

"But it is an interesting thing to think about. How many people use Consumer Reports when buying a new TV or car? I mean, I do. I haven't bought a car in 20 years without referencing Consumer Reports," he said. And yet at present, there's no equivalent for consumers to assess the quality of pharmaceutical products, in part because quality is so much more difficult for consumers to understand, particularly relative to other industries where defects may be readily apparent. "Sub-visible contamination is one example, but there are many other examples of where quality is not observable [by consumers]," he added.

"It's a very tough industry for you folks to run. It explains why it's so important to maintain quality every day to maintain the safety and efficacy of these products."