Sites Can Take Cues from Good Manufacturing Practice to Improve Trial Quality
While the clinical research and drug manufacturing sectors operate under mostly different priorities, they share a commitment to quality management. And with manufacturers’ long history of operating under quality management regulations from the FDA, drug- and devicemakers have developed some best practices clinical trial sites are adopting to improve their culture of quality.
“What’s slowly happening is the GMP quality is coming over into GCP, which I think is a good thing,” Susan Leister, vice president for quality and compliance at Technical Resources International, told CenterWatch Weekly. “CAPA [corrective and preventive action] systems, deviation [investigations], overall SOP management — sites should have all of those things in their quality system.”
Consultant Leslie Sam of Leslie Sam & Associates, agrees. Sam, who formerly worked for Eli Lilly on the research and manufacturing sides, said that while both had quality objectives in the form of policies and procedures that needed to be followed, there was a very different work ethic on the manufacturing side.
“Clinical research was very action-oriented, more reactive and more about addressing the issues, whereas in manufacturing, they were also focused on preventing that issue from happening again,” Sam said. “I’m not suggesting that clinical was operating in this reactive mode to the exclusion of proactivity, because that absolutely is not the case. But in manufacturing, they just did it as a part of how they approached getting their work done. And it wasn’t just the quality people in manufacturing, it was all the employees. I could describe it as quality was more of a devotion, a conviction,” Sam said.
One of the main concepts that sites can pick up from manufacturers is change control — keeping a record of alterations in procedures and documents — an idea that is expressed frequently throughout regulations for drug and device manufacturing.
Sites must, at a minimum, get hold of the change control process to avoid costly disruptions to clinical research, according to Susan Schniepp, distinguished fellow at Regulatory Compliance Associates. “Any time you’re making a change to a document,” Schniepp says, “you need to have a change control system in place to accommodate making those changes, justifying and explaining them. Every time we change a form, an SOP or a process in manufacturing, there has to be a rationale and a reason behind it so there’s accountability. You have to show that the change wasn’t just implemented because somebody said so.”
Receipt of investigational product and other trial supplies is a key area that can benefit from the kind of quality control processes manufacturers use to check incoming ingredients and components, Schniepp adds. “That procedure should certainly include matching what was shipped with what was received,” she says. “You’re going to have to match the label, the expiry date, the lot number — there’s going to be label information that should be checked in. The printed version of the label should be checked against the bottle version, as should the date of manufacture.”
Schniepp said this information should be checked against the site’s master records, which she described as akin to a drugmaker’s master batch record — a detailed description of the process a manufacturer uses to make a product.
Sites also should consider enacting procedures for investigating unusual circumstances or deviations, such as equipment or logistical failures. Investigation of deviations or nonconformances is a requirement in GMP regulations.
A site should investigate why, for example, a shipment of heat-sensitive product for use in a clinical trial was left on a receiving dock in direct sun for several hours.
“There should be some sort of procedure in place that allows the site to formally investigate when things go wrong, when there are deviations,” she says. “Because no matter how well you lay out your SOP and how well people follow them, there will be deviations that need to be investigated. If you don’t investigate those kinds of glitches thoroughly and come to some sort of root cause, it could compromise the clinical trial material when there’s no reason for that to happen.”
While some FDA rules — such as the software validation requirements outlined in 21 CFR Part 11 — are applied across both the research and manufacturing sectors, some differences in priorities exist between GCP and GMP, Leister says.
Both sectors focus on data integrity, she says, but “there will be a little bit of a different slant between the two because sites and GCP are focused on human subject protection, and the GMP universe is focused on product quality.”
Training on data integrity principles should be included as an SOP for sites just as it is in manufacturing.
“They need to spell out how they handle their paperwork, what their signoff hierarchy is, how their paperwork flows and the chain of custody of the paperwork to maintain its integrity,” Schniepp says. “They need to be shown how to make corrections, whether that’s in a database or on paper. There needs to be a proper way to correct an error that’s been made and to capture that change for accountability, making an audit trail. That’s really what sites need to be trained on.”
Expectations across the research sectors are changing, Leister says. Sites increasingly are expected to have a general CAPA procedure similar to the principle described in device manufacturing regulations.
And risk management is receiving a lot of attention on the clinical trial side. Leister says some of her sponsor clients encourage their sites to implement risk management processes outlined in the International Council on Harmonization’s GCP guideline, ICH E6(R2), despite the fact that the guideline expressly gives that responsibility to sponsors. In another sign of change, Leister says she is starting to see quality agreements, long an area of focus in GMP, beginning to appear in trials as well.
Aside from GMP quality practices creeping into the GCP sector, sites can also look to manufacturers for ways to improve their institution’s overall quality culture. Sam — who worked for 15 years in clinical research, compliance and quality before switching to five years in manufacturing quality — says employees on the manufacturing side consistently acted on quality matters. Every business meeting had an item about quality on the agenda.
“There might be an update on implementation of a CAPA, or the status of a risk that was being managed,” Sam says. “My takeaway was that everyone in manufacturing felt personally accountable for quality and compliance.”
Liz Wool, president of the Wool Consulting Group, advocates for the same kind of attitude in clinical trial staff. Employees at sites need to be able to identify problems and understand their role in making corrections and improvements. “That ability,” she says, “has to be welcomed by the organization,” which, for sites, would be the principal investigator, managers and other managerial staff. “The organization then needs to coach employees on how to evaluate a situation and bring a solution forward. If somebody has a concern about quality or subject safety, they need to be able to say that it needs to be addressed,” she says.
Wool adds that quality is everyone’s responsibility and emphasizes the importance for companies to invest in their employees’ personal development, whether in GCP or GMP. “When you invest in people’s development and retention, doing all the right things at the right time and putting the right people in the right job, that illustrates a quality culture. But until we understand that these employees are not just a head count but a valued member of our team with a distinct role and accountability for quality, we truly will not get to a quality culture.”