Preparing for an FDA Inspection in a Global Pharmaceutical Environment

Foreign inspections have long been part of FDA's efforts in ensuring medical product safety and quality. In fact, FDA has been conducting foreign inspections for the past 50 years. It is through such foreign inspections that the agency monitors the manufacture of pharmaceutical products and ingredients that are imported into the United States. The primary goal of the inspections is to ensure that foreign establishments meet the same requirements as domestic establishments in regards to the quality, purity, potency, safety, and efficacy of pharmaceutical products marketed in the US. If a foreign pharmaceutical manufacturing establishment fails to meet FDA's cGMP standards—based on an inspection or otherwise—the agency has the legal authority to deny products manufactured at the violative facility entry into the US.

James R. Johnson

FDA officials acknowledge that the agency is far from achieving foreign drug inspection rates comparable to domestic inspection rates. Each year, however, FDA investigators are appearing more frequently at the doors of foreign manufacturing facilities. For example, between 2007 and 2009, FDA inspections at foreign pharmaceutical manufacturing establishments increased by 27%. The agency seems to have no intention of slowing down—FDA has created a dedicated cadre of foreign drug investigators and established permanent offices in Europe, China, India, Central and South America, South Africa, and the Middle East.

The US government's increasing focus on foreign inspections should come as no surprise. Pharmaceutical manufacturing has become more global, and the US market has, in turn, become more reliant on foreign medical products. Based on FDA's estimation:

• 40% of finished drugs, 80% of APIs, and 50% of all medical devices are currently imported.

• There was a 13% increase in pharmaceutical products imported into the US between 2002 and 2009.

• From 2000 to 2007, the importation of "high-risk" medical products, such as vaccines, quadrupled.

• In 2002, there were just over 500 FDA registered foreign drug-manufacturing establishments. That number grew to more than 3000 in 2007, and registered foreign establishments now outnumber registered US establishments.

• In 2000, the US imported roughly $1.7 billion more in biopharmaceutical and pharmaceutical products than it exported; by 2008, that gap grew to $18 billion.

Because of the dramatic increase in the volume of imported drug products and the increasing complexity of the global supply chain, FDA is operating as an internationally-focused consumer safety agency. In doing so, the agency is pressing forward with increased foreign inspections, as well as partnering with foreign counterparts to create global coalitions of regulators focused on ensuring and improving global product safety. A clear result of which has been the significant increase in Warning Letters and Untitled Letters issued for international drug quality issues—in 2005, three such letters were issued; in 2010, FDA issued 23.

As FDA's focus on foreign pharmaceutical manufacturing increases, it is critical that non-US facilities be prepared for an FDA inspection more than ever, particularly those establishments that have no—or limited—experience in dealing with FDA. Therefore, if your facility manufactures abroad for the US market, it is important to keep the following guiding principles in mind when preparing for an FDA inspection.

IMPLEMENT AN INSPECTION SOP

The first step in preparing for an FDA inspection is implementing an SOP that will govern employee activity during the inspection. This should be done whether or not an FDA inspection is anticipated. The SOP should provide guidance on a number of issues, including: greeting the FDA investigator, duties of key individuals, conducting tours of the facility, responding to FDA questions and requests for documents, employee documentation of the inspection, and inspection-closeout procedures.

When FDA schedules the inspection, obtain as much information as possible. FDA's foreign inspections are announced in advance, and are generally scheduled for a predetermined period of time. So when FDA schedules the inspection, obtain as much information from the agency as possible. The more that is known about a planned FDA inspection, the better. Specifically, determine the reason for the inspection (e.g., cGMP, preapproval, followup, or for-cause), when the inspection will start, how long the inspection will last, whom from FDA will be attending, and whether there are any special requests or documents to have ready. As soon as notification of the FDA inspection is received, alert the company's regulatory affairs, quality, and legal departments.

ESTABLISH AN INSPECTION TEAM

Once the dates of an FDA inspection have been established, make certain all crucial employees will be available during the inspection. Carefully select an inspection team that will be tasked with interacting with the FDA investigator. Part of this exercise is knowing who is crucial; knowing who is currently responsible and who was historically responsible; and ensuring that employees understand their responsibilities. One of the worst things that can happen during an FDA inspection is having an unqualified or unprepared employee answering vital questions posed by the investigator.

REVIEW AGENCY GUIDANCE AND LEARN FROM OTHERS' MISTAKES

Prior to the inspection, review all the relevant and recent FDA Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) guidance documents and compliance policy guides, as well as the International Conference on Harmonization (ICH) Quality Guidelines. These documents are key to understanding FDA's often-evolving view of industry standards, which is as important to comply with as FDA's specific cGMP regulations. Additionally, it is helpful to analyze past Warning Letters and available Form FDA 483s; these documents offer valuable insight into what FDA investigators are keying on during inspections and what issues investigators deem to be worthy of a Form FDA 483 observation.

ORGANIZE AND REVIEW DOCUMENTS

Ensure that all required documents are available for FDA inspection, and make sure they are organized, complete, and current. Reviewing key documents will allow employees to refresh their memory and understand the organization of documents. It is also advisable to have an English translation of critical SOPs and documents, if possible.

DISCUSS INTERNALLY ANY KNOWN DEFICIENCIES

Bring any known deficiencies to light; especially any that may relate to prior Form FDA 483 observations or recurring issues. The goal is to avoid any surprises during the inspection, as well as taking any preemptive steps to correct or mitigate the deficiency prior to the FDA inspection.

PLAN FOR ANSWERING INVESTIGATOR'S QUESTIONS

First and foremost, all employees need to be directed to be honest and to avoid any speculation. Of equal importance, be prepared to speak with one voice and avoid internal disagreements while in front of the FDA investigator at all costs. Also, employees should be instructed to ask for clarification if FDA's questions are not completely understood (e.g., be clear on what timeframe FDA's request for documents covers). This is important so that all questions and requests are fully addressed, while at the same time refraining from saying more than what is necessary. Employees should also understand that it is acceptable to take a reasonable amount of time in responding to the investigator's questions and requests; responses do not always have to be instantaneous.

CONDUCT A MOCK INSPECTION

Generally, the best way to prepare for an FDA inspection is to actually practice one. This can help pinpoint any weaknesses in procedures or inadequacies in records, and it prepares employees for the types of questions that will be asked by the FDA investigator. Another benefit of practicing an inspection is—by providing a dry run for employees—they will be more comfortable when the actual FDA inspection occurs. The mock inspection should be scheduled far enough in advance to afford time to implement any corrective actions which become needed as a result of the mock inspection.

HAVE A ROOM RESERVED FOR THE INVESTIGATOR

While a simple matter, always set aside a quiet and securable conference room or office for the FDA investigator to review documents and to conduct his or her business. Ideally, this room should be away from any high-traffic employee areas, as well as the manufacturing areas.

An FDA inspection is an important event and should not be taken lightly. This is particularly true for non-US facilities that manufacture biopharmaceuticals, pharmaceuticals, and APIs for US importation. In these cases, the legal standard for FDA to refuse the entry of drug products into the US is significantly lower than what is required for FDA to initiate a domestic enforcement action (i.e., a seizure or injunction). FDA can refuse admission of an imported drug product if the product merely appears to be violative.

One way a drug product can appear to be violative—and therefore be denied entry into the US—is if it was manufactured at a foreign establishment that had a poor FDA cGMP inspection. Therefore, taking the time to carefully prepare the items discussed above, in advance, can greatly reduce any tension and increase the likelihood of a positive FDA inspection.

James R. Johnson is an associate at Hogan Lovells US LLP, Washington, DC, tel: 202.637.5600, james.johnson@hoganlovells.com.