The FDA released an interesting draft guidance on July 12, 2013 on the circumstances involved when a company delays, denies, limits or even refuses a drug inspection. This refers to GMP inspections of drug manufacturing and has been released in light of the issues with compounding pharmacies in the US and drugs that were not of adequate quality as well as a follow up required in the FDASIA law.
The document can be found at: www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf
Background
This guidance is an outcome of the July 2012 FDASIA law. One section of the law defines a drug product to be adulterated if it “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.” Adulteration usually leads to market recall or withdrawal.
So although this refers to GMP and factory inspections, the interest for us in the drug safety world is really to get an idea of what FDA considers non-compliance with inspections of pharma companies.
The FDA has the authority to perform inspections by duly appointed employees of FDA or designated officers. They have the right to “enter, at reasonable times, and inspect, at reasonable times and within reasonable limits and in a reasonable manner facilities under the jurisdiction of the FD&C Act”. This has been upheld in court cases. The law also “makes refusing to permit entry or inspection and refusing to permit access to or copying of any record…prohibited acts.”
Delays in Scheduling a Pre-Announced Inspection
Delays may be reasonable and may be due to circumstances beyond the control of the company. Many of FDA’s inspections are unannounced. However, many are announced, particularly preapproval inspections and ex-US inspections. For these, the FDA will contact the company and work out an acceptable date for the visit. FDA cites weather, security issues, holidays and other local issues as valid reasons for delay. Unacceptable behavior includes:
- “Failure to agree to a proposed inspection start date and does not give a reasonable explanation for its failure to do so
- After scheduling an inspection, the company requests a later start date without giving a reasonable explanation
- The company fails to respond to FDA’s contacts.”
Delays During an Inspection
Once the inspection has started, FDA regards actions by the company (or its agents, employees etc.) as unacceptable that “impede an FDA investigator at the inspection site from performing the inspection in a reasonable manner may be considered delaying the inspection” and thus producing significant negative consequences for the company.
On the other hand, “FDA is aware that its appearance on-site may initially cause some minor confusion and/or inconveniences to the facility’s employees. Minor delays that result from good faith efforts by the facility to comply with FDA requests generally would not be considered unreasonable.” This is a slight understatement. FDA’s appearance often produces major anxiety and even chaos and panic though hopefully companies have now realized that FDA and many other health agencies can and will show up for detailed inspections at any time. FDA cites two examples of unacceptable behavior:
- “A facility does not allow the FDA investigator access to an area of the facility until a specific future date or time even though the area is operational…
- A facility leaves the FDA investigator in a conference room without access to necessary documentation or responsible individuals for an unreasonable period of time that interferes with the investigator’s ability to complete the inspection.”
Not only is the latter example unacceptable it is simply bad behavior in general for any visitor. It also would allow the inspector to leave the room and walk around unescorted which is generally not a good idea.
Delay Producing Records
“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.”
Unlike manufacturing situations, drug safety inspections do not revolve as much around looking at the physical plant so much as examining records, documents and files. There is no excuse for failure to produce documents (electronic or paper) rapidly upon request, particularly if copies are stored in the “cloud” or on a server anywhere in the world.
Denial of Inspection
This is the most interesting of the situations FDA describes. Denial is defined broadly to mean any behavior to prevent FDA from conducting or completing the inspection. “This includes statements or physical actions intended to avoid inspection or to mislead or deceive the investigator. “ (emphasis added). Note that the FDA no longer calls its “auditors” inspectors but rather “investigators”; this is an unfortunate choice as there may be some confusion with “clinical trial investigators”. Examples include rejecting FDA’s attempts to schedule an inspection, not allowing the FDA to begin a scheduled inspection and not allowing FDA to inspect the facility because certain staff members are not present.
The last example has application to drug safety inspections. Often, in a large organization, one or more individuals are out of the office for various reasons and are not available physically for an interview by the inspectors. Sometimes this can be arranged by phone or videoconference but sometimes the person(s) are simply not available. The company needs to find someone who can respond to the inspectors’ questions. Absence of a key individual is no excuse to stop or delay an inspection.
Limiting Access to Facilities
This applies primarily to physical access to the manufacturing site but a few of the examples would apply to a drug safety inspection. Examples include the company:
- Limiting or refusing direct access to parts of the process
- Limiting an interview or review to an unreasonably short length of time
- Limiting direct observation of the process or restricting entry to the inspector or forcing the inspector to leave before the inspection is completed.
Usually in drug safety inspections, the physical plant is not as critical as how the safety information is handled and processed. Nonetheless, restricting the inspector from examining an unkempt or out of control file room or desks full of confidential cases have been noted during inspections. Many companies will put the inspectors in a conference room not physically located in the drug safety department but rather a short distance away or on the floor above or below. This alleviates staff anxiety to a degree but also prevents “loose lips” from inadvertently saying things the inspector should not hear. The inspectors will usually want to tour the drug safety area but they do not physically need to work there.
Limiting Access to or Copying of Records
This is actually a major issue in some FDA inspections. Sometimes companies will refuse to make certain documents available. The question is then which documents does the FDA inspector have the right to see and which can be withheld. This is addressed in 21 U.S.C. 374 which states that FDA CANNOT examine “financial data, sales data other than shipment data, pricing data, personnel data (other than data as to qualification of technical and professional personnel performing functions subject to this chapter), and research data (other than data relating to new drugs, antibiotic drugs, devices, and tobacco products and subject to reporting and inspection under regulations lawfully issued…”
For drug safety this means that financial and sales data are off limits. Personnel information is also off limits except for documentation of training and skills such as CVs, job descriptions and training/continuing education documents. The controversial area that is still often up in the air relates to internal and external audits and inspections of drug safety and pharmacovigilance. In the EU, the law clearly allows access. In fact, audits must be kept in the PV System Master File available to the inspectors and EMA/member states’ competent authorities. For FDA this is still not fully resolved. Some inspectors ask for and receive such audits; others don’t ask or receive. Some companies refuse access to the audits or make brief summaries available or will read the results to the inspector but not actually physically show them to the inspector.
The FDA cites as problems, refusal to make available requested records or making available records that are “unreasonably redacted”.
Refusal to Permit Entry or Inspection
This is another area that is more germane to manufacturing rather than to drug safety inspections. However, the issue can arise indirectly if the FDA comes to the wrong physical location to do a drug safety inspection. As a rule, FDA comes to registered sites – sites that actually exist and are identified to FDA. Often, however, companies move and shift personnel as business needs change. The drug safety group may be moved (as happened to me several times) to other buildings on the campus or even to temporarily leased offices a few miles away. In the worst case situation, the whole drug safety unit is moved to another city or even country.
If FDA shows up for an unannounced inspection (or, worse, an announced inspection) only to be told that drug safety moved to Chicago or Mumbai, this news will not be well received by the inspectors. Being told the drug safety unit is 4 miles down the road or in building 6 not building 9 is usually no problem at all but far away is a problem. Although this will not likely cause a citation it will not make the inspectors’ job easier and may make for a testy inspection.
Lessons to be Drawn
FDA expects and demands full cooperation from the company and personnel being inspected. Failure to make available personnel, facilities, documents and even the operational aspects of the inspection (demo of the computerized safety database, source documents, photocopy machines) will certainly make the inspection unpleasant and may even lead to citations in the 483.
Keep in mind also that GMP inspections or pre-approval inspections that are not primarily aimed at drug safety or pharmacovigilance may still produce a visit to the drug safety department by the inspector at the end of the primary inspection to be sure that the product quality complaints were made known to drug safety (particularly those with an AE as part of the quality issue) or that the SAEs/SUSARs from the clinical trials were properly handled by the company and submitted to FDA.
As always, the bottom line here is to be ready for an inspection, have a well-oiled SOP in place, ensure that the personnel involved know how to handle the inspection and treat the inspectors graciously.
