The US Food and Drug Administration (FDA) is out with a new draft guidance for industry establishing a framework by which a pharmaceutical manufacturer may delay, deny, limit or refuse an inspection of a facility by FDA.
The draft guidance, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection, released 12 July 2013, comes almost exactly one year after the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA), which established that FDA inspectors could administratively detain products they believed to be adulterated or misbranded.
[For a full explanation of FDA's authority under the law, please see Regulatory Focus' 12 July 2013 story, "Proposed Rule Establishes Administrative Detention Process for Pharmaceuticals."]
While that authority was contained within Section 709 of FDASIA, a similar provision contained within Section 707 of the act amended 21 USC Section 351 - the statute that covers the definition of adulterated drugs - to include the products of any establishment that delays, denies or limits an inspection, or refuses to permit entry or inspection.
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 decrease the incentives to delay or obfuscate 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, but with one caveat: FDA would have to, within one year of the passage of FDASIA, release a guidance document detailing what the statute means by "delaying, denying, or limiting inspection, or refusing to permit entry or inspection."
A 'Reasonable' Guidance
While the guidance document may be a few days later than legislators had intended, FDA has now nevertheless released that document, establishing the definitions called for in the statute, including examples of each behavior. However, FDA immediately makes one important caveat: "FDA does not interpret the four terms describing prohibited behavior necessarily to be mutually exclusive," meaning that companies may find their product adulterated under the statute in more than one way depending on their 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."
While FDA concedes that delays may result from reasonable factors-showing up at 2 a.m. hoping to inspect a facility might not result in anyone actually being there to grant entry, for example-FDA said it is often in the practice of giving advanced notice to a facility's management team to facilitate the inspection process.
"FDA's goal is to contact facilities within a reasonable time prior to the proposed start date of the inspection," it wrote. "FDA will make reasonable accommodations for local conditions, such as weather or security situations, holidays, and other non-work days, and scheduled manufacturing campaigns."
Factors to Adulteration
However, FDA said it envisioned several factors constituting a delay under this pre-inspection announcement process:
- if a facility does not agree to a proposed inspection data and does not give a reasonable explanation for refusal
- if a facility attempts to reschedule the date of an inspection and fails to give a reasonable explanation
- if a facility fails to respond to FDA's attempts to contact it
Once inspectors are granted access to the facility and begin the inspection process, other behaviors will also 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."
"Although FDA 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 be considered delaying the inspection," it wrote. However, the terms "reasonable" and "timely" are not defined, leaving them up to FDA's discretion.
The guidance also notes that an outright denial of inspection will be defined as falling under one or more of four scenarios:
- a facility rejects FDA's attempt to schedule an inspection
- a facility does not allow the FDA investigator to begin an inspection of a facility, even if it has been pre-scheduled
- a facility does not allow the FDA investigator to inspect the facility because certain staff members are not present
- a facility does not allow the FDA investigator to inspect the facility by falsely alleging the facility does not manufacture drugs
- In addition, FDA said it would determine that a facility has "limited" its inspection if any of the following events occur:
- a facility orders the discontinuation of all manufacturing for the duration of the FDA inspection without a reasonable explanation
- a facility states that direct observation of the manufacturing process, in whole or in part, must be limited to an unreasonably short amount of time, thus preventing FDA from inspecting the facility as is usual and customary
- a facility limits direct observation of portions of the manufacturing process
- a facility unreasonably restricts entry to a particular facility without adequate justification
- staff at a facility causes the FDA investigator to leave the premises before the inspection is completed.
- an inspectors' ability to photograph areas of a facility that are deemed to be necessary to effectively conduct a particular inspection is restricted
- a facility refuses to allow the FDA investigator to review the facility's shipping records that FDA has authority to inspect
- a facility provides some, but not all, of the records requested by the FDA investigator that FDA has authority to inspect.
- a facility provides the FDA investigator the requested records that FDA has authority to inspect, but the records are unreasonably redacted
- a facility refuses to provide records that FDA requests pursuant to section 704(a)(4), or such records are unreasonably redacted
- sample collection (environmental, finished products, raw materials, in-process materials, or reserve samples) is restricted or prevented
Finally, FDA said that in the most extreme cases, 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 to contact it (especially if there is "clear evidence" of employees being presently engaged in job-related functions).
Comments on the draft guidance are due in 60 days, or on 15 September 2013.
Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection
Federal Register Document