Quality Culture Assessments and Records Request Responses

FDA Regulator Panel Discussions: Part II

Quality culture and issues with responses to FDA records requests performed in lieu of inspections were prominent topics during the “Inspection-Based Panel Discussion” at the September 2021 PDA/FDA Joint Regulatory Conference.

[Related: For more on quality culture, view the recent Redica Systems webinar, “The Past, Present, and Future of Quality Culture,” featuring Regulatory Compliance Associates’ Susan Schniepp.]

• Part I of this three-part article examined discussions at the conference around data integrity with special attention to analytical instrument audit trails and the use of consultants.
• Part II below focuses on discussions at the PDA/FDA conference around quality culture and concerns voiced by FDA officials regarding responses to record requests and the scope of remediation efforts for issues identified during inspections.
• Part III will provide a synopsis of comments made at the ISPE Annual Meeting held in person and virtually in Boston a few weeks later by FDA CDER Commander (CDR) Tara Gooen Bizjak in response to a question asking what she sees as significant new or emerging global compliance issues.

How is Quality Culture Assessed?

Center for Veterinary Medicine (CVM) Supervisory Chemist Mai Huynh, one of the moderators of the PDA panel discussion, noted that recently there has been a lot of emphasis on quality culture and its role and importance in maintaining a robust and effective quality management system (QMS). She asked the FDA panelists what the agency looks for during an inspection to determine if a company has an acceptable quality culture.

FDA Center for Drug Evaluation and Research (CDER) Office of Compliance Global Compliance Branch I (GCBI) Branch Chief Quallyna Porte responded, “It is very clear when you walk into a facility if the leadership from the top-down has a quality mindset. It is very visible in how the firm operates and how the personnel interact with any investigators.”

She emphasized that one of the aspects is leadership involvement—leadership driving quality within a facility. “And when I talk about quality, I am not just talking about quality as in a quality assurance organization, but the overall facility, because I truly believe quality is the responsibility of everyone at the facility and not just those in a quality organization.”

Rachel Harrington, Consumer Safety Officer in FDA’s Office of Medical Products and Tobacco Operations added that as an investigator she would try to determine whether employees at all levels within a company can explain how the products they are involved in making are used and what impact it has on patients.

“It is really important in a mature quality system for everyone in the company, not just those at the top, to be involved in understanding why it is so important to build quality into the product,” she commented.

Harrington also stressed that it is important to make sure there is timely and effective communication to raise quality issues to the appropriate levels of management. And that includes, when necessary, the decision-makers—usually upper management.

Another question that an investigator may ask, she said, is, “Does management look to proactively strengthen their quality management system by identifying and reviewing new and revised regulations and guidance, or looking for trends in industry that may be pertinent for their operations? In other words, not just reacting to problems but trying to prevent them upfront.”

Executive Involvement and Documentation

Program Expert and Drug Specialist in CDER’s Pharmaceutical Quality Program Branch Sandra Boyd added, “When I am out doing an inspection, one of the things I note is transparency. Mistakes happen. We have all been there. Often it is human error. What is important is how you address and handle mistakes. When I stumble upon a big issue that was kind of hidden, that is when I start getting concerned. Was there an investigation? Follow the path.”

CDER Office of Manufacturing Quality (OMQ) Office of Compliance (OC) Manufacturing Guidance and Policy Staff Director CDR Tara Gooen Bizjak provided her perspective.

She explained that some of the elements Harrington discussed looking for are related to “data-driven” work that has been done by PDA and St. Gallen University to identify elements of a quality culture that are indicative of a firm with a positive manufacturing output and track record of quality. “I think that there have been a lot of improvements in the last five years or so,” she commented.

It is very clear when you walk into a facility if the leadership from the top-down has a quality mindset

Gooen Bizjak explained that although quality culture is not in the regulations, “it is something that is indicative of a strong QMS and something that FDA is looking at now and will be even more in the future based on some data-driven approaches.”

She pointed out that FDA Warning Letters have also been emphasizing the critical role of executive management and overseeing the health of the quality system. “Vigilant oversight is extremely important,” she said. “Top management sets the tone, sets the policy, and that all impacts and influences the rest of the company.”

[Editor’s Note: Learn how pharmaceutical leaders can use change to build a mature quality culture.]

Record Request Responses Reflect Transparency

Section 704 of the FDA Safety and Innovation Act of 2012 (FDASIA) grants the agency authority to request pharma company records in preparation for or in lieu of an inspection. The increased use of that authority during the COVID-19 pandemic and the quality and content of the records received was a discussion topic during the FDA panel.

CDER’s Porte commented that “we are in very unprecedented times with COVID-19. So, we are relying a lot more on the rules that we did not previously use, such as [section] 704 records requests.”

She noted that in response to records requests FDA expects “full transparency,” i.e, “complete and accurate information.” She conceded that while the expectation “probably sounds very simple,” she has seen many issues in response to records requests.

When I stumble upon a big issue that was kind of hidden, that is when I start getting concerned

“We have had instances—and this is not just once or twice—but several instances where we send questions to the firm and the questions are simple in our minds with a ‘yes’ or ‘no’ answer—for example, ‘Do you have process validation? If you do, please provide.’ Somehow firms find a way to respond without being direct.”

[Editor’s Note: For more on records requests, read the article, “Desk Inspections, Missed Action Dates Take Place of FDA In-Person Site Visits.”]

Porte also recounted “instances where we have had to go back three or four times to request information. Sometimes we need to have meetings just to ascertain or to obtain a simple answer to a question.”

“When we send those requests out, if you do not have information, we are looking for you to be upfront and say you do not have any. If you do, then provide it to us so that we can proceed. Transparency and complete and accurate information will be helpful.”

Panelists Urge Firms to Clarify Requests

CDER’s Boyd also weighed in on the topic, emphasizing, “If you do not understand a request, please clarify before you start to send records, particularly if you know that a specific request is going to be burdensome.”

For example, she said, if the response is going to involve hundreds or even thousands of records—which the agency has seen—“just make sure that the FDA representative is aware of what is being asked for, because they might think it is something simple and it turns out not to be.”

“And I would say in most cases that they will be able to adjust their request. If they receive hundreds of thousands of records, it means they have to review all of those records. They will probably be able to adjust it, so it is more specific in terms of what exactly that they are looking for.”

She pointed out that FDA warning letters have also been emphasizing the critical role of executive management

Porte also addressed agency experience with documentation sent in response to warning letter citations.

“We have situations where the volume of information that a firm sends in and the organization of that information or the lack thereof is definitely one of the challenges,” she explained.

“Some firms are submitting tons of records to us, but they are not organized in any way. We have to spend so much time trying to dig through it to get the information that we need. We want to encourage firms to provide their responses in a structured format so it is easy for us to follow and easy for us to understand and appreciate all the good work that has been done. Just from an organization standpoint, that is one challenge.”

Scope of Remediation Needs Consideration

FDA Branch Chief Porte also discussed issues with responses to requests when manufacturing deficiencies are identified during FDA inspections and remediation is required—specifically the scope of the resulting remediation efforts.

“Some of the challenges that we encounter in that area is that firms are not looking at the issue that we have identified holistically to appropriately define the scope of their remediation,” she said. This indicates that the firm did not perform a comprehensive assessment of the gaps the agency identified.

“When we go out to do inspections, we are only there for a short period. We cannot identify all the issues at the facility. We are only capturing a snapshot. What we expect the firm to do is to look at the issues we have identified from a systemic standpoint and identify where the gaps are and ensure that the remediation encompasses all of that and not just what we identify.”

CVM Senior Policy Advisor Laura Huffman added her perspective on the topic.

“I want to agree with everything that CDER said, but also reinforce that this principle is applicable not only to regulatory meetings and warning letters, but to 483s in general—ensuring that changes and corrections are not focused solely on a very specific area, as was mentioned, but instead looking more broadly at what enabled the concern to occur and taking that next step to be proactive.”

“Often, we see a very narrow issue effectively addressed without taking a step back to see the bigger picture and what is really a sign of the firm’s quality culture.” 

[Related: To learn more about quality culture, download the recent Redica Systems webinar, “What is the Past, Present, and Future of Quality Culture?”]