This article will focus on the processes and approaches followed by the U.S. Food and Drug Administration to fulfill its statutory obligations to enforce its regulations and to protect the well being of the American public.
Unlike domestic facilities, foreign companies are notified in advance about the intent of the Agency to perform an inspection. So, because of the advance notice, the target company will benefit from approximately 6-8 weeks to prepare its staff, facilities, and processes for the upcoming event. That level of preparation includes advances review of documents such as deviation reports, internal investigations, specific batch production records, logbooks, process validation reports, and complaint records that have a high probability of being subjected to review by an FDA investigator. Following the review and selection of potential documents that are expected to undergo FDA challenge, subject matter experts have the opportunity to rehearse and prepare the way in which a topic will be discussed during the inspection.
In addition to the review of documentation and related activities, companies will make sure that their facilities are in a good state of repair and that maintenance and calibration activities are up to date. To ensure the facilities, equipment, and personnel operate in a consistent level of cGMP compliance pre-inspection, companies will perform daily, surprise tours covering all production shifts and will do “on the spot” challenges of the personnel on the shop-floor.
Another significant difference between domestic and foreign inspections performed by the FDA consists of the amount of time allocated to specific facilities. In the U.S., inspectors can stay for as long as they deem it necessary until they are fully satisfied with the coverage performed on systems, processes, and activities. For a foreign inspection, time allocation is limited with the inspection of sterile manufacturing activities granted seven calendar days of coverage. However, prior to conducting an inspection, FDA will make an extensive request of documents and data that allows the inspectors to “initiate” the inspection prior to arrival at the site.
While there is a certain level of implied advantage for foreign companies to proactively prepare for FDA inspections, the number of FDA-483s, Warning Letters, and import detentions issued indicate that the pre-announcement of an inspection does not always result in positive outcomes. Warning Letters from the U.S. FDA confirm that, year after year, foreign companies continue to struggle with establishing a consistent self-sustaining state of quality and compliance, with the following as the areas of highest level of vulnerability and exposure:
- Limited power within the Quality Assurance organization to achieve adequate oversight of activities and enforcement of internal policies and procedures;
- Inadequate quality systems;
- Data integrity issues due to the lack of adherence of personnel to good manufacturing practices and poor supervision;
- Inadequate document management systems, both hard copy and electronic; and
- Inadequate investigation programs which in turn result in the implementation of inadequate corrective and preventive actions.
Daniel Barreto is vice president of the compliance practice at Lachman Consultants. He has both government and industry knowledge having served in multiple roles and responsibilities, including FDA investigator, compliance director, and vice president of quality, managing pharmaceuticals, medical devices, biological products, and DDC products.