In-process QA soon may be standard for research

Here comes PAT

In a never-ending quest to make clinical trials safe for participants and learn from unfortunate incidents that may have occurred during a clinical trial, the Food and Drug Administration is not only scrutinizing corrective and preventive action plans (CAPA), but also looking outside of health care for effective quality assurance processes.

Specifically, the FDA is interested in the concept of process analytical technology (PAT) in which there is a continuous quality assurance check throughout the clinical trials process, rather than saving this check for the end of the process.

Currently, the FDA web site lists a definition for PAT as follows: a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

"Through PAT you are looking all along at which process can be more cost effective and safer," says Sandy Weinberg, PhD, senior director of Fast Trak GE Healthcare in Atlanta. "Then you know it’s safe and the final check is a confirmation."

The FDA is expected to complete a final draft of guidelines for PAT within a year or two, he notes.

"Anyone who is FDA-regulated ultimately should look to see whether it’s applicable," Weinberg says. "The first place it will be applied is with the manufacturers; secondly, the labs and, third, clinical trials."

Improving risk analysis

Besides adopting PAT, clinical trials managers also may improve process quality through improving their risk analysis process.

"There are two ways of thinking about risk methodologies and using risk control to improve quality, costs, and to improve regulatory compliance and regulations," says Victoria V. Lander, market development manager for NuGenesis Technologies of Westborough, MA.

"People use the terms risk analysis and management interchangeably, but they’re not the same thing," she says. "Risk analysis is the overall process of stepping out and thinking — whether in clinical trials, manufacturing, or quality control — and figuring out the risks or hazards that could or do occur."

According to the FDA, CAPA procedures consists of these basic steps:

  • Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data.
  • Investigating the cause of nonconformities relating to product, processes, and the quality system.
  • Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems.
  • Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device.
  • Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems.
  • Ensuring that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems.
  • Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.

Tips for improvement

Lander and Weinberg offer these strategies for improving CAPAs and PATs:

• Document risk assessment. A documented risk assessment and risk analysis should show how each critical system fits into the overall picture, Lander explains.

For example, for a 21 CFR Part 11 compliance, the idea is to make certain all electronic records and signatures are reliable and legally defensible, she says.

"Put different controls in place," Lander adds. "Some are stringent and require major system revisions."

However, if a clinical trials manager has decided that a particular system or process is low risk, then it’s unnecessary to go through the extensive process of replacing the system, she says.

"You might put procedural controls in place — something not as expensive and resource-consuming," Lander says.

Then when the FDA conducts an audit, it’s crucial to have a documented risk assessment that justifies the actions taken to control the risks in that particular system, she says.

• Develop a cost-effective strategy for processes. "The FDA’s new focus is on making sure there’s a cost-effective strategy for any regulation," Weinberg says.

Many pharmaceutical manufacturers already follow this strategy for their manufacturing process, but it’s not always employed in the clinical trials process, he says.

"Every once in a while you hear in the news that a trial is halted because the results are so dramatic, and that’s what we’re talking about — make adjustments as you go along," Weinberg says.

"This is a codification of good policy," he says.

• Write standard operating procedures. The first thing to do to either create or improve a CAPA is to write standard operating procedure (SOP) guidelines for how to proceed with each step of the process, Lander suggests.

"A lot of companies create risk management files and put in the results of everything they do and then assign a risk index, a probability of occurrence, and severity of consequences," she says. "So they’re ultimately assigning value to every system: high, medium, low, or a numbering system."

For guidance on writing SOPs, review published risk management protocols in and outside of the clinical trial world, Lander says.

Also, it’s a good strategy to form a cross-functional team, consisting of a quality manager in a contract research organization, a professional skilled in regulatory issues, and others, to decide which type of risk management protocol will be put in place, she says.

There are many different types of protocols that could be reviewed, including ones used in the aerospace industry, the military, the food industry, and others, Lander adds.

Some examples include the failure mode effects and criticality analysis, which is from the aerospace industry, and the hazard analysis and critical control points from the food industry, she notes.

"Look at the protocols, and if you like them adopt them wholeheartedly," Lander says.

• Don’t overlook the simplest approach: training. One of the simplest ways to manage risk is to make certain clinical trials staff are well trained, she says.

"Think about the fact that people who are running these trials need the background and experience to do it," Lander says. "One of the simplest ways to control risks is to make sure the key personnel have the right background and are trained and then document the training."

In short, the risk management process might be reduced to these steps: make certain people understand the process, monitor their progress, standardize the approach, train people, identify the right tool for the right job, and validate the equipment, she summarizes.

"That’s the basic structure for a quality plan," Lander adds.

• Be proactive with instituting PAT. "Too often in our industry, we become reactive instead of proactive," Weinberg says. "Nothing hits the radar screen until the FDA announces it, and then we are surprised."

But in the case of PAT, clinical trials managers have an opportunity to be proactive. They have two or more years to prepare for the inevitability of putting PAT in place, he adds.

"I think PAT is a logical approach, and it’s often used in our industry without that name, and it is an appropriate way to produce critical research in a cost-effective way," Weinberg says. "The whole industry is gearing now to understand that cost is an important factor.

"We used to be a cost-plus industry where we cared about quality and whatever it cost we would spend," he says. "Now we need to maintain the quality and at the same time use cost control measures to make sure we are at a place where people can afford the kinds of products our quality produces."