Health safety has become one of the most important issues among the people of America. It is directly related to the quality of food and pharmaceuticals. FDA envisions in having the utmost safety of the food quality as well as the safety and efficacy of all pharmaceuticals and that the public health is advanced and protected. Its mission of protecting consumers and enhancing public health, demands the need of careful inspections of regulated facilities to determine a firm's compliance with regulations and the Food, Drug and Cosmetic Act. Inspections in pharmaceutical manufacturing facilities on the basis of compliance with cGMPs are a vital element of drug quality control and are therefore one of the intrinsic ways FDA protects the public health. It provides a platform to control and enforce compliance with general good manufacturing practices (GMP) and authorize the manufacture of specific pharmaceutical products, normally in relation to an application for marketing authorization. FDA holds the authority to inspect any facility in order to review the manufacturing, handling and packaging process and investigate whether the drugs are adulterated, misbranded, or in non compliance of cGMP guidelines and the Food, Drugs and Cosmetics Act. Any attempts made by the manufacturing facility or the person in charge that could intend to obstruct an FDA investigator from inspecting the site before and during the inspection, would be considered as an attempt to delay the inspection. In order to create clarity on the circumstances that may cause deliberate delay of a drug inspection, FDA has currently issued guidelines related to non compliance with drug inspection of a facility.
On July 9, 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144) was signed into law. Section 707 of FDASIA added 501(j) to the Food, drug, and Cosmetic Act (FD&C; Act) to deem adulterated a drug that has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection. Section 707(b) of FDASIA demanded the Food and Drug Administration (FDA), not later than one year after the date of enactment of FDASIA, to issue guidance that defines the circumstances that would constitute delaying, denying, or limiting inspection, or refusing to permit entry or inspection, for purposes of section 501(j). Therefore, the draft guidance, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, released on 12 July 2013, comes almost exactly one year after the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA), establishing a framework by which a pharmaceutical manufacturer may delay, deny, limit or refuse an inspection of a facility by FDA. It says that obstructing facility inspections can result in drugs being found adulterated and can further result in detainment of such drug products by the FDA investigators.
FDA analyses that in the past, some firms have sought to refuse or delay entry of FDA inspectors into their facility, hoping the additional time could be used to either clean up a facility or expunge certain records. In September 2012, for example, FDA released a Warning Letter to a Chinese company that reportedly threw FDA inspectors out of the manufacturing facility after they began uncovering a host of serious deficiencies.
In order to prevent the delay or obfuscation in the inspection process, FDASIA's provisions were intended to give FDA the authority to automatically deem as adulterated any product manufactured at such a facility.
While the guidance document establishes the definitions called for in the statute, including examples of each behavior, FDA immediately has made one important caveat stating that it does not interpret the four terms (delay, deny, limit and refuse) describing prohibited behavior necessarily to be mutually exclusive. This means that companies may find their product adulterated under the statute in more than one way depending on their behavior. Therefore, the behaviors described in the scenarios of the guidance document may be examples of more than one type of prohibited behavior. The operative phrase used by FDA in other parts of the guidance is "reasonable." The agency, FDA writes, is authorized by statute to "enter, at reasonable times, and inspect, at reasonable times and within reasonable limits and in a reasonable manner, facilities under its jurisdiction." FDA mentioned that its goal is to contact facilities within a reasonable time prior to the proposed start date of the inspection. It will make reasonable accommodations for local conditions, such as weather or security situations, holidays, and other non-work days, and scheduled manufacturing campaigns.
FDA may (and often does) contact a facilitys management in advance and pre-announce an inspection with an intention to facilitate the inspection process and ensure that appropriate records and personnel will be made available. Still, the delay may occur for many reasons. While talking about the delay of an inspection, FDA said it envisioned several factors constituting a delay under this pre-inspection announcement process such as the facility, does not agree to a proposed inspection data and does not give a reasonable explanation for refusal; attempts to reschedule the date of an inspection and fails to give a reasonable explanation; or fails to respond to FDAs attempts to contact it. This causing of delay of an inspection may lead the drug to be deemed as adulterated under section 501(j) of the FD&C; Act. Also, once inspectors are granted access to the facility and begin the inspection process, other behaviors can constitute a delay, FDA wrote. These include failing to allow an inspector to access part of a facility despite it being operational (and within FDA's jurisdiction), the facility failing to provide access to the necessary documentation or knowledgeable personnel, or delaying access to documentation for an unreasonable period of time that interferes with the investigator's ability to complete the inspection.
In the guidance FDA mentions that although it recognizes that facilities require a reasonable amount of time to produce records requested, especially if the records are maintained at a different site, a delay in producing records to FDA without reasonable explanation may again be considered as delaying the inspection. However, the terms "reasonable" and "timely" are not defined, leaving them up to FDAs discretion.
Next FDA talks about the denial of inspection interpreting the term deny to include active behavior by the owner, of a drug facility to prevent an authorized representative of the FDA from conducting an inspection or to prevent FDA from completing an inspection. The guidance also notes that an outright denial of inspection will be defined as falling under any one or more of four scenarios which may be that a facility, rejects FDAs attempt to schedule an inspection; does not allow the FDA investigator to begin an inspection of a facility, even it has been pre-scheduled; does not allow the FDA investigator to inspect the facility because certain staff members are not present; or does not allow the FDA investigator to inspect the facility by falsely alleging that the facility does not manufacture drugs.
Further, FDA states that the owner of a drug facility who prevents an authorized representative of the FDA from conducting an inspection to the extent allowable under the law may be viewed as limiting the inspection under section 501(j). This may include denial to disclose or permit observation of the manufacturing processes; not allowing photography; not allowing access to or copying of records that FDA is entitled to inspect by law and; restricting collection of samples, allowable under the law such as environmental, finished products, raw materials, in-process materials, or reserve samples.
Finally, FDA said that it will determine that a company has refused its inspectors entry if the inspector is barred from entering either the whole facility or parts of the facility, if the facility does not respond to any attempts made by FDA to contact it or if the facility does not answer calls from the FDA investigator who is present at the facility especially if there is clear evidence of employees being presently engaged in job-related functions.
The examples that are used in the guidance, illustrate the most common situations that FDA has encountered in preparing for and conducting inspections as well as situations that FDA anticipates may occur, rather than serving as an exhaustive list. By the means of this guidance and the amended provisions in FD&C; act, FDA looks forward in fulfilling its mission of protecting the public health by assuring the safety, efficacy, and security of biological and medical products as well as the food supply and cosmetics.
