Posted 21 October 2014
By Alexander Gaffney, RAC
The US Food and Drug Administration (FDA) has put the finishing touches on a new policy intended to ensure the companies it regulates aren't able to hide problems from it during the course of inspections.
In July 2013, FDA released a draft guidance document, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection seeking to clarify its newfound authority under the Food and Drug Administration Safety and Innovation Act (FDASIA).
Under Section 707 of FDASIA, FDA is authorized to deem a product adulterated if its manufacturer, processor, packager or warehouse "delays, denies or limits an inspection, or refuses to permit entry or inspection."
Prior to the passage of the rule, 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. FDASIA, legislators hoped, would create a more equitable system in which FDA could immediately punish companies not complying with its attempts to inspect a facility.
FDA's July 2013 draft guidance was industry's first glimpse at how legislators' authority would be interpreted and put into practice by FDA.
Among the most important points made by regulators was that they intended to enforce the policy based on a "reasonable" interpretation, which had been mentioned in the statute. Accordingly, FDA said it would seek to enter and inspect facilities at "reasonable times and within reasonable limits and in a reasonable manner." In plain terms: FDA almost certainly won't be conducting inspections at 2:00 am or trying to access documents to which it has no right.
"FDA will make reasonable accommodations for local conditions, such as weather or security situations, holidays, and other non-work days, and scheduled manufacturing campaigns," the agency added.
The guidance also explains what members of industry do have to worry about during an inspection. For example, FDA said if a facility fails to respond to FDA attempts to contact it, FDA will consider that to be an unreasonable delay. Similarly, if a facility attempts to reschedule the date of an inspection without a "reasonable explanation" or otherwise goes not agree to a proposed inspection, FDA will also consider those to be unreasonable delays.
Once FDA obtains access to a facility, a plethora of actions can constitute a "delay" under FDASIA. For example, if a company doesn't allow an inspector to access part of a facility, records, or staff members for "an unreasonable period of time," FDA can consider the company's products adulterated.
Once again, FDA's guidance stressed a "reasonable" interpretation of the statute. "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" were not defined in the guidance, leaving them up to FDA's discretion.
"First, Let me Take a Regulatory Selfie…"
Notably, FDA's guidance also for the first time established that FDA staff would have the right to "photograph areas of a facility that are deemed to be necessary to effectively conduct a particular inspection." Failure to allow this photography will result in a facility's products being deemed misbranded, FDA said.
Some companies, however, said this provision could threaten their intellectual property rights, and asked for a narrowed interpretation to be instituted in any final guidance document. Other legal experts wondered aloud if the photography provision might stand up to legal scrutiny if challenged in court.
Guidance in Action
FDA's guidance has been referenced in at least two Warning Letters in the last two weeks.
In one letter to a Chinese pharmaceutical manufacturer, FDA said the company had refused to provide access to records regarding product sampling. FDA's own subsequent testing found the products to contain an unidentified ingredient, sildenafil, which is approved in the US under the brand name Viagra.
A second letter cited yet another Chinese company for preventing FDA's inspectors from accessing parts of the manufacturing facility. Requests for batch production records were repeatedly denied, FDA claimed. The few records that were provided to FDA indicated the company was using suppliers subject to FDA import alerts, the agency said.
Final Guidance: What's Reasonable?
FDA's final guidance is in many ways similar to its draft guidance, but contains several changes the agency said was meant to clarify parts of the guidance and respond to concerns raised by industry.
For example, the final guidance—a full two pages longer than its draft predecessor—includes a lengthier explanation of what FDA considers a "reasonable" inspection to be:
"Although the FD&C Act does not specifically define “reasonable,” FDA has long maintained that the inspectional authority under Section 704 of the FD&C Act “extends to what is reasonably necessary to achieve the objective of the inspection.” FDA intends to work with facilities to conduct inspections and procure the information necessary to achieve the objective of the inspection. FDA will consider reasonable explanations for behavior that may otherwise be considered to be delaying, denying, limiting, or refusing an inspection."
Indeed, many of the examples within the guidance are geared toward explaining what levels of “reasonableness” FDA might tolerate. Under one example, if a manufacturing facility only runs one campaign per month, FDA would be willing to reschedule a visit so that it coincides with the manufacturing of that month's campaign.
In another example, FDA said it would be fine with delayed access to an area if it were done to allow an inspector to comply with the facility's documented gowning procedures, often done to prevent contamination. Elsewhere in the guidance FDA explains that for records not kept in English, it would not consider translations not being readily available to be a "delay" under FDASIA.
In other cases, FDA said it would be patient with companies it requests "sufficiently large" volumes of records from, apparently understanding that finding those records takes time.
Photography Section Changed
While FDA's section on photography garnered perhaps the most attention out of any section in the guidance, the final version is meaningfully similar to the text contained in the draft guidance.
For example, FDA's draft guidance contained the following line:
Not allowing photography by an FDA investigator may be considered a limitation if such photographs are determined by the investigator(s) to be necessary to effectively conduct that particular inspection.
That language has since been replaced with:
Impeding or resisting photography by an FDA investigator may be considered a limitation if such photographs are determined by the investigator to be necessary to effectively conduct that particular inspection.
One major clarification, however, is contained in the final guidance: FDA now says that a company will now be allowed to object to FDA photographing an area if the photograph would "adversely affect product quality."
The guidance also now contains a list of possible uses for photography, though FDA notes the list is not meant to "limit" FDA inspectors.
Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection (FR)
Comments on the Guidance