Preparing for FDA Inspections in a Changing Regulatory Environment

Manufacturers and regulatory experts expect major transitions in inspections and enforcement. Contributing to this environment are the US Food and Drug Administration's strong focus on product and process quality (see Figure 1), increasing numbers of global business partnerships, and complex product technologies.

During an investigation, FDA can review everything "from [the] receipt of raw material through manufacture and any component associated with laboratory testing" as well as "anything required or self-imposed by the firm to move through the manufacturing stages," according to Michael Rogers, director of the Division of Field Investigations in FDA's Office of Regulatory Affairs.

Figure 1: FDA's quality system model.

Although the path to compliance with current good manufacturing practices (CGMPs) was never meant to be a one-size-fits all strategy, there are some compliance issues that year after year continue to plague manufacturers. Cited observations relating to quality control, out-of-specification results, process validation, sterility assurance, and contamination continue to be of top concern (see "Fast facts" sidebar and Figure 2).

Fast facts (FY 2006)

"It seems like these are the same things I've seen for the past 20 years," says John C. (Jack) Garvey, vice-president of compliance and quality management at The Weinberg Group (Princeton, NJ). "Part of the reason is that investigators, even when they are using systems-based techniques, are still relying on the traditional methods of information gathering through the negative-product experience—looking at product failures, deviations, and product complaints."

Figure 2: Top 10 drug observations used in FDA Turbo Establishment Inspection Report*, as of July 1, 2007.

Regardless of the situation leading to an inspection, industry and regulatory experts agree on several basic factors to take into account during preparation.

Conduct a thorough risk assessment

Although good manufacturing practices (GMPs) have for the most part remained the same since the 1970s, increased computerization and automation since that time means that risk assessment has taken a systems-based approach.

Industry's role. Industry is taking a more proactive look at ensuring well-characterized quality systems—those systems for which the link between process requirements and their influence on product quality is well understood and scientifically sound. Companies still must ensure that their standard documents as well as training and operating procedures are in place, but it is now in the context of control-focused documentation. A company must ensure that an investigator understands the application of the quality system to its product and the link between that documentation and essential product requirements.

"You can't just focus on the details and the particulars of doing something," says Chris Smith, vice-president of regulatory affairs and quality at AAIPharma (Wilmington, NC). "Instead you focus on creating a process that will ensure quality every time."

Companies must make the investment to develop the good science, the proper product and process characterizations, the properly derived quality system and product-control frameworks. "Companies are still not getting the essence of good product and process characterization and how it drives into a risk-based control framework to make sure we are really controlling the things that are critical to the product build," says Garvey.

An FDA inspection team will have these concepts in mind. "FDA likes to see risk management or risk assessment introduced in the decision-making process regarding things like change control, product release, and product recall," advises Peter D. Smith, vice-president of pharmaceutical compliance at Parexel Consulting (Lowell, MA). "Inspectors get an impression from a company if they talk about a risk approach in decision-making. It's good for them to hear."

The risk-assessment plan involves getting everyone in the company on the same page. As a former FDA investigator, Carmen Medina performed more than 200 inspections. Now a principal at Tunnell Consulting (King of Prussia, PA), she says it's easy to sense disparities between various operating units, even before walking into an inspection site, based solely on a company's documents. These disparities often are related to quality standards or prevalent risk within the company. In many cases, companies might focus on making sure pivotal batch records and corresponding data are acceptable.

Investigators are trained to perform what's called a top-down assessment. "Twenty years ago, investigators walked in looking at inadequacies in individual documents and manufacturing deviations and how those deficiencies impacted products in the field. Today, we're looking at, 'What is the level of risk in a company that could potentially impact every single product within the entire operation?'" says Medina.

This difference is important because it means each division in a company needs to be on the same page in terms of the level of risk they are facing and how seriously it should be taken. For example, a quality unit may seem to be more stringent when it comes to the release of a batch that underwent a manufacturing deviation than the head of manufacturing might be because they place the deviation in a different perspective than quality assurance. Or a manufacturing unit may be more concerned about limited resources than the company's executive management might be. These conflicting priorities must be recognized and reconciled before an inspection begins.

FDA's role. It is too early to ascertain how FDA's most recent risk-based initiatives such as process analytical technology and quality by design will affect inspection preparation. Two opposing approaches to quality, one solidified in ensuring sameness and the other based on process understanding, are resulting in "a great deal of conceptual, scientific, and regulatory uncertainty," says Garvey. "If the agency is serious about moving these initiatives forward, they are going to have to be highly tolerant of mistakes and missteps of companies along the way."

One of the major issues for the agency is one of follow-through, notes Garvey. "If the agency doesn't provide an extremely consistent, aligned approach between how they actually conduct the inspections and their publicly stated intentions, any progress made to date will be in jeopardy."

Do your research

"Failures don't just come from noncompliance with the regulations, but also out of industry expectations and industry standards," says Medina. Even though industry expectations are not yet codified into law, investigators may inspect against them and against that particular trend.

For this reason, there is an entire body of documentation that any company preparing for an FDA inspection should study beforehand in addition to CGMPs. "Review professional publications and go to conferences," advises Medina. "Obtain all the pertinent CBER [Center for Biologics Evaluation and Research]and CDER [Center for Drug Evaluation and Research] guidances and compliance programs. Get your hands on FDA's investigator inspection manual and read the preapproval inspection (PAI) sections. Obtain any recent 483s issued in situations specific and similar to your industry. If you're a small or big manufacturer, read about those that apply to you so you begin to know what the FDA investigator is scanning for when they walk in. They prepare before heading to your site, so you should as well."

Peter Smith agrees that paying attention to guidances, even if they're not technically enforceable, is crucial to passing an inspection. "Any good investigator can make a tie from a failure to follow a certain guidance to a true GMP deficiency," he says.

Think globally

"It's unprecedented right now what's happening globally from a risk-management perspective," says Medina. "We've had over 10 risk-management guidances or global initiatives in the past three years—that's huge. Risk management is on everyone's minds." In preparation, many companies expect to address risk management according to quality guidelines issued by International Conference on Harmonization (ICH) in addition to those issued by FDA.

Seeking conformance to international regulations is critical when preparing for inspections from other countries' regulatory agencies such as the European Medicines Agency. "Europe, Japan, Brazil, and others are all using similar ICH guidelines, even World Health Organization or PIC/S guidelines, so it's important to pay attention to them," adds P. Smith.

ICH Quality Guidelines (i.e., Q7, Q8, Q9, and Q10) are receiving increased attention. Addressing product development, quality risk management, and quality systems, respectively, these guidelines help to put frameworks around some of the issues important to FDA and to other international regulatory agencies.

"We are hoping companies will read and study these documents and find out how to use the concepts within them as they operate their program of drug discovery, development, assessment, and manufacturing controls," says Nicholas Buhay, deputy director of the Division of Manufacturing and Product Quality in FDA's Division of Manufacturing & Product Quality in the Office of Compliance. "We hope through harmonization to make our operations more efficient for industry while still providing valuable approaches to manufacturing, manufacturing control, and development that will make a more certain and reliable product."

Pay attention to overseas operations

Preparing for an overseas inspection may require more time and, in many instances, extra resources than preparing for a local inspection. In addition to reviewing FDA's international inspection guide, there are several unique points to keep in mind.

For example, for inspections in non-English speaking countries, have an interpreter on site. "Sometimes there are misunderstandings caused because a proper English word is not used or because the question is not clearly understood. Use an interpreter to make sure things are clarified," says P. Smith.

"It's also a good idea to have an English translation of critical documents and standard operating procedures (SOPs)," adds P. Smith. "They don't have to be official, but good translations on items such as change control, deviation investigations, and validation reports are important."

FDA has more stringent standards when it comes to imported goods. "The law doesn't provide us the authority to go to another sovereign jurisdiction and do what we want there," explains Buhay. To remedy this, investigators can use an "appearance standard" rather than "a full conformance standard," he says. "We can refuse a product's entrance if it appears to violate the law."

Overseas inspections are announced and are usually for a shorter, predetermined length of time. "One of the flexibilities you don't have in the foreign arena is to extend the inspection. These trips often involve multiple firms and commitments to inspect other sites the following week," explains Rogers. "We also need to have the data and management available before we arrive."

International inspections are often shorter also due to the additional resource burden, adds Buhay. "We can't go out as frequently as we would like to. On the other hand, we prioritize pretty effectively. We are getting to places that matter according to the conditions that apply, like risk and the impact of drugs on the US market."

Get data in order

Table I outlines the most common documents FDA will request during a PAI, including those that are CGMP requirements and those that are not necessarily required by CGMPs but that will be expected. An inspection team should not be given access to financial documents such as sales or revenue reports or forecasts, internal and supplier audit reports, or personnel files, except for employee education and training information.

Table I: Typical documents requested during FDA preapproval inspections.

Have an organizational chart on hand as well, suggests Garvey. "A facility diagram that is coded by environmental control area can help the agency get an idea of where they are when doing plant tours, what the controls in those areas are and how they relate to product manufacturing builds."

Review SOPs

Reviewing and updating standard operating procedures will not only help the inspection team understand how things operate but also will provide staff with a refresher course on protocol and procedure. This will enable them to better discuss and explain systems when asked.

Who is at the door?

Carry out a mock inspection

The best way to prepare for an FDA inspection is to carry out a mock inspection ahead of time.

Set a timeframe. It's best to carry out an inspection close enough to the scheduled inspection that all the data and procedures are fresh but far enough ahead of time that one can correct any errors or make any adjustments before the big day, advises P. Smith. This is generally about six to eight months before the scheduled inspection.

Make staff assignments. Inspections are a mobilization effort, and all personnel must know what his or her role will be and what is required. "It's important to assign a trained, key employee to each subject area to the PAI such as management responsibility, R&D, pilot plant, the water system, validation, production, engineering, laboratories, quality, change control, and regulatory affairs," advises Chinny C. Okparanta, president of Integrated Quality Systems (Edison, NJ).

Don't forget the basics.

Ideally, an internal readiness team made up of personnel with FDA inspection experience and who have interfaced with FDA investigators or were on the regulatory side of the industry is important. "All strategy should be driven by this core team of people who know how to manage the process," says Medina.

Practice interviewing. Surprisingly, a number of inspection failures have less to do with actual facility management and more to do with simple misunderstandings. Although contract manufacturers are constantly going through customer audits and thereby are accustomed to answering questions and retrieving documents, other companies may have very complex systems to explain that are new to an FDA inspector. Staff must be able to explain everything in basic terms, with flow charts and summaries to demonstrate systems.

"Often times, the staff is so familiar with the subject matter that they don't understand the investigator hasn't been to the plant before and may not understand certain terminology," says P. Smith.

It is also important to be able to explain each employee's responsibilities and how the operations are managed. According to Rogers, "The compliance program serves as a recipe for our inspectional process, but for a PAI and especially for an initial inspection, we go through a complete history of the firm's operations, management, management structure, and responsibilities to get an idea of the firm's general operations as well as an understanding of the products they make." During a company's first inspection, adds Rogers, the team should be prepared to talk about the other products the company manufactures beyond the one under review.

Implement a remediation plan

After the mock inspection, companies should "seize the opportunity to enhance all the critical compliance categories that have been identified as deficient by your mock FDA inspection team and address them," says Medina.

For a PAI, one best practice is to eliminate any disparities that might have arisen since the time the submission was made and the time the PAI is to occur. "Information about the facility, manufacturing processes, QC methods, batch record, corresponding equipment, and anything substantive reported in the submission must be consistent with what the investigator will find and inspect against during the PAI," adds Medina. "The biggest reason for failure is the disparity identified by the investigator between what was reported in the regulatory submission's CMC [chemistry, manufacturing, and controls] section and what is actually found on the manufacturing floor and within laboratories."

Applying these strategies should go a long way toward a successful inspection process. "Overall, be forthright in making the appropriate people and records available to support your data," says FDA's Michael Rogers. "We're just trying to do our job. We have a role in public health to protect people, and so does the industry."

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