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Agnes Shanley is senior editor of Pharmaceutical Technology.
Just as FDA strengthens ties between reviewers and plant inspectors, proactive manufacturers are involving different disciplines in preparation for FDA audits.
FDA continues to strengthen its approach to plant inspections (see Sidebar), scoping out roles for inspectors and reviewers, and how they should interact (1). Former FDA investigator Christopher Smith, now a consultant with The FDA Group, shared with Pharmaceutical Technology best practices and things he wishes more pharmaceutical companies would do to prepare for an FDA inspection.
PharmTech: What impact will recent changes at FDA have on inspections?
Smith: All these changes should benefit industry, FDA, and the consumer. Years ago, when I began my career at FDA, inspectors were frustrated by the disconnect between FDA’s field organization, the Office of Regulatory Affairs (ORA), and the chemists, microbiologists, clinicians, and others in headquarters who were reviewing new drug applications.
In some cases, we would inspect a company’s plant and find cGMP issues, and then issue a 483 to the company. While we worked with the firm on resolving the issues in that 483, we’d sometimes see that the same company had already issued a press release touting approval of its new drug, made at the facility with all the problems. We often wondered why one side of the agency wasn’t communicating more closely with the other.
That communication has been steadily improving since FDA started the preapproval inspection program in the 1990s, and funding has been reserved to allow reviewers to accompany inspectors on some inspections, or at least to talk to them and, for example, give them a list of top 10 priorities and what to look for, based on their application under review.
However, these advances have been complicated by the fact that application sponsors today are outsourcing more development, manufacturing, pakaging, and clinical research. Applications have gotten very complex, but any contract partner named in a drug application is subject to inspection and should be ready.
Sidebar: Teamwork and specialization to govern facility inspections
FDA Communications Manager Jeremy Kahn addressed questions about how FDA is changing its approach to facility inspections with Pharmaceutical Technology.
PharmTech: How will FDA change the way it inspects pharma plants?
Kahn: FDA’s Program Alignment plan, established in 2013, aims to modernize and strengthen FDA’s ability to keep pace with the acceleration of scientific innovation, global expansion of markets, and new programmatic mandates. On May 15, 2017, the agency announced a new organizational model, in which the entire reporting chain for the Office of Regulatory Affairs’ (ORA) inspection and compliance staff, from employees on the front lines to the assistant commissioners at headquarters, would specialize in a particular commodity, for example focusing on pharmaceutical quality operations.
This model represents a significant change from ORA’s previous geography-based model, where employees, regardless of their area of expertise, may have worked in more than one program area. We anticipate that deepening knowledge by specialty area will strengthen ORA’s ability to regulate an increasingly complex and global industry. This approach also ensures that management and compliance can efficiently address issues as they arise.
PharmTech: How will departments within FDA be connecting and communicating with one another?
Kahn: FDA’s Center for Drug Evaluation and Research (CDER) and ORA are implementing a new, historic concept of operations agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. The new operating model will be a key element of meeting the commitments under the Generic Drug User Fee Amendments II to communicate final surveillance inspection classifications to facility owners within 90 days of an inspection. FDA will begin to implement this agreement this fall, applying it to all human drugs, in order to more quickly meet this commitment.
PharmTech: Is there still too much emphasis on the clinical side and getting approval, rather than ensuring cGMP compliance?
Smith: There’s still a disconnect in industry between the chemistry, manufacturing, and control (CMC) or the cGMP and facilities side of the application process, and the clinical side. If I do an audit of a clinical investigator site or a sponsor facility’s clinical program, to help them prepare for an FDA inspection, when I ask questions about the CMC side, representatives from the clinical side are often oblivious to the issues that may have occurred when making or packaging the product.
I see this disconnect not so much at virtual companies but at the larger pharma companies. Typically, there will be a vice-president of clinical research, a number of physicians, pharmacologists, statisticians, and other teammates all focused on clinical studies, patient safety, trial protocols, institutional review board oversight, and data capture, but when you ask about manufacturing, you’ll sometimes receive a blank stare, even though GMP issues could affect the results of the clinical study.
PharmTech: What are some ways in which FDA is eliminating the disconnect between its staffers that industry might emulate?
Smith: One crucial change has been using appropriate expertise to do the audit, and making audits more of a team effort. The agency has realized that, for example, if an aseptic facility must be inspected, it might be best to have someone with a microbiology background handling it. Similarly, an engineer might be selected to look at water systems and piping, as well as specialized equipment with advanced control features.
PharmTech: Do you take a crossfunctional team with you for mock audits?
Smith: I try to convey the need to do that, but typically companies are concerned about cost and they’ll just want one person to do the audit for two days.
PharmTech: How should companies prepare for a mock audit?
Smith: One key suggestion is to be more transparent within their organizations, and with the mock auditors, about what their problems have been. FDA can’t look at everything, and an audit is really only a snapshot of what they have seen that day.
For a new drug application (NDA), a company has likely spent years developing this product and has lots of data. FDA then comes in and pulls a batch record or the results of a study and audits it. Their inspectors are trying to find out where the problems are. They have the authority to ask for all deviations and batch failures. People don’t want to show their dirty laundry.
You may have good quality systems in place, but FDA inspectors want to know whether your systems can address problems effectively when things go wrong. The only way you can prepare for that is by knowing where all your skeletons are before a mock audit. Look for problems and see whether and how they were addressed, and be able to explain that clearly.
For FDA, the key question is not whether you had the problem but what you did about it. Unfortunately, people usually want to focus on their successes. FDA may want to believe them, but they are, after all, cops on the beat. They won’t pull you over to say ‘You’re a great driver,’ but because they want to issue a speeding ticket. Companies need to prepare for that.
PharmTech: How do you typically set up the audits?
Smith: When I perform mock audits with fellow consultants, clients often ask us to pretend to be FDA inspectors. However, very early in the audit, it often becomes clear that their employees aren’t addressing things as they should. In such cases, we need to stop, take our FDA hats off, and coach them. In some cases, they may not be explaining the reason for an issue clearly, or may have the wrong person explain it. So the audit becomes a continuous ‘hats on, hats off’ exercise. In most cases, their employees have never been through an inspection and have no idea what to expect.
PharmTech: Where have you seen the greatest improvement in getting companies to understand FDA’s expectations during an audit?
Smith: One of the biggest things I’ve been able to help companies do is to review how they’ve managed and documented the handling of problems that have come up in the past. We’ll often look at an investigation report, either a lab failure, manufacturing deviation, or a clinical site problem, that happened a while ago.
They’ll show what happened and dig out some kind of report, but what becomes very clear is that the decisionmaking around resolving the problem was poorly documented. Three years ago, everyone understood why the decision was made, but key staffers have left and businesses have changed, so now people are looking for complete documentation and can’t find answers. The documentation must be clear and complete during the problem resolution stage, if it is to be clear years later.
PharmTech: How can managers be sure they’re answering the right questions?
Smith: As product development progresses, it is crucial to stay on top of things. You don’t want to discover problems after you’ve filed the NDA. You need to have difficult conversations with staff and contract partners before filing, and relevant documentation must be in order.
PharmTech: Are companies taking a team approach, internally, to audits?
Smith: We are starting to see more firms doing internal audits with teams, where, for example, the quality assurance department does a mock audit of a key operation, but brings in a manufacturing operations expert, an engineer from metrology, and an IT staffer to help. After all, quality assurance staffers can’t be experts in everything.
PharmTech: How often should mock audits be done?
Smith: It depends on the complexity of the product and the size of the operation. For instance, an oral solid-dosage form manufacturer who has filed many NDAs will have fewer challenges when filing an NDA for a traditional process than a manufacturer who is using a new process and new equipment. The new process will likely require more frequent audits.
PharmTech: What should companies do when they are working with vendors overseas that may be used to less stringent regulatory oversight?
Smith: The most important thing to clarify with FDA is how you handle vendor selection, auditing, and monitoring. It’s amazing how often sponsors don’t check on day-to-day performance of some of their contract partners. Recently, I just worked with a mid-sized company that had filed an NDA, and half way through clinical studies they found that the offshore contract research organization (CRO) they were working with was doing a poor job. They could have caught problems earlier if they had been paying attention. Strong selection and oversight are crucial.
And this goes for subsidiary contractors too. One company had hired a contractor to handle its water treatment issues. When I asked about this contractor, the plant manager handed me four lab notebooks. There were no signatures or any other signs that anyone from his company’s quality department had been observing and signing off on this contractor’s performance. These are the kinds of things that prevent you from being in control, and they’re red flags for FDA inspectors.
1. FDA, “Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations,” fda.gov, June 6, 2017
Vol. 41, No. 10
Pages: 64-66, 88
When referring to this article, please cite it as A. Shanley, “Teaming Up for FDA Inspections," Pharmaceutical Technology 41 (10) 2017.