Despite the fact that in 2018, the FDA formally changed its guidance framework regarding biologics inspections from every two years to a risk-based schedule, the fact is that inspections continue to occur in order to ensure that every new drug and medical device manufactured meets safety and efficacy needs, and that manufacturers uphold high quality standards in the U.S. and overseas.
So what exactly is involved in an FDA inspection and how can Contract Development & Manufacturing Organizations (CDMOs) best prepare for one? Consider the following.
The FDA switched to a risk-based schedule in order to help speed approvals of essential drugs, as well as because of limited resources. The old requirements mandated facilities be inspected at least once within 2 years of being registered, and then at least once every two years after that. With the new risk-based schedule, it is given to higher-risk facilities, such as those producing more complex drugs, or those with the potential for greater risk to consumers.
According to the FDA, it can only approve an ANDA (Abbreviated New Drug Application) or NDA (New Drug Application) if the methods, facilities and controls used for the manufacture, processing and testing of the drug are found adequate to ensure and preserve its identity, strength, quality, and purity.
Virtually every type of an API manufacturer – from finished dosage manufacturers and testing sites to primary packaging and labeling sites – are on the FDA inspection radar. While their frequency will depend on risk-based factors, any manufacturer with new facilities, or one that files an application for a new chemical entity can be pretty much guaranteed one.
The FDA conducts inspections of facilities all over the world, and essentially any facility that intends to either ship or market drug substances or drug products to the U.S. If an inspection is determined to be needed, the FDA will send a team of individuals to conduct the inspection. The team may include: investigators, other specialists, chemistry experts, microbiology experts, a process/facility expert and a formulation expert.
Once an application is submitted to the center, The inspection team will determine if the site is ready for commercial manufacturing, and if so, if the application information is complete and accurate. In the past, inspections usually entailed a few days of having inspectors on-site, yet today, they’re usually on-site for two weeks on average. While there, they will review sampling plans, testing of components and evaluate the facility and equipment procedures with a focus on contamination controls.
As part of FDA inspections, the quality system for batch release will be evaluated. Inspectors will focus on laboratory system Standard Operating Procedures (SOPs); personnel; training and stability data; as well as evaluate test methods and impurity profiles.
An FDA inspection is not a save-the-date-type of an event. It very often is unscheduled with no long-term notice. For this reason, CDMOs should always be prepared, as though an inspection is occurring each day.
During any inspection, the first three things inspectors ask for right away are the following:
In the past few years, another requirement that can be added to this list is proof of data integrity. With heightened awareness of data manipulation infractions, especially among some overseas manufacturers, this is becoming a key focus.
Regardless of the uncertainty of when an FDA inspection will occur, there are measures and standard operating procedures that CDMOs can take to avoid a fire-drill, or maybe even a failed inspection. Below are a few:
Conduct an Internal audit. By conducting your own routine facility and employee training audits, as well as reviews of key systems, such as preventative maintenance and clean room operations, you can uncover areas that need improvement. These audits can be performed by your own staff, but they’re often more productive when they involve an independent consultant who can see things from a different perspective.
Training. All staff should be routinely trained on new procedures, equipment and changing requirements. For thorough training plans, you should first perform a routine gap assessment to measure each person’s level of current training against a predetermined standard or matrix of responsibilities.
Data Analysis. Regular analysis of your data, documentation SOPs and computer systems is critical to identify systemic weakness. For this to be effective, you should first identify quantifiable metrics or key performance indicators (KPI) for critical systems and processes.
The FDA Form 483 notifies the CDMO of objectionable conditions found during an inspection. It’s presented and discussed with the company’s senior management, and it’s expected that you will respond to the Form 483 within 30 days in writing, outlining a corrective action plan. This could entail fixing a systemic issue or quality system or how you will better adhere to your SOPs. If there is no response to the Form 483 and no corrective action taken, a warning letter is issued, which is the first step to the shut-down of a facility.
FDA inspections are as inevitable as the tides, but knowing what to expect and having the right processes in place from the beginning, can help you pass them with flying colors.
If you have questions related to how and when to best prepare for FDA inspections, give us a call at Seqens North America CDMO: (978) 462-5555.