Formal on-site inspections and audits are a tool used by regulatory health and environmental protection authorities to assess a regulated organisation’s compliance with applicable regulations. These inspections of facilities manufacturing regulated products or performing other regulated activities, are based on well-established rules, laws and regulations.

During such on-site inspections, the inspectors are entitled to request access to all documents, records and areas connected to the performance of regulated activities. In order to achieve the objectives of the inspection the fill cooperation of the organisation being inspected is required.

New Provision

However, despite these laws and regulations some inspectors do sometimes experience difficulties in securing the full cooperation of management and staff of the facility being inspected. These problems have ranged from facility management and staff denying access to certain rooms or documents, to completely refusing to allow the inspection to be performed.

As such activities can seriously undermine the entire inspection process; in 2012 the United States Congress amended the Food, Drugs and Cosmetics Act by adding a new provision to section 501 which deems a regulated 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.

This new provision creates potentially serious consequences for a regulated business that obstructs an inspector in performing his duty, which could include not being able to sell products manufactured in the facility where management and staff have sought to obstruct an inspection.

This article will discuss the conduct than may be considered, by the regulatory authorities, to constitute obstruction of an inspection and will use examples that have been cited in warning letters and other regulatory actions to illustrate the prohibited activities.

In addition, this article will also discuss some of the explanations which may be acceptable to the authorities as a reasonable excuse or explanation for otherwise prohibited conduct during an inspection.

The United States Food and Drug Administration (FDA) published a final ‘Guidance for Industry’ on the ‘Circumstances that Constitute Delaying, Denying, Limiting or Refusing a Drug Inspection1’ in October 2014 which discusses the activities, or lack of, that may constitute obstructing an inspection. This guidance creates four different categories of conduct that can obstruction of an inspection. We will discuss each of these categories below.

Circumstances that may Constitute Obstruction of Inspections

Delaying Inspections

Delaying inspections can occur when a company unreasonable prevents or delays an inspection from commencing or proceeding in a customary manner. These can be divided into three subcategories:

Delaying Scheduling of Pre-Announced Inspections

Which may result in drugs being deemed to be adulterated, can occur when a company will not agree to a proposed inspection date, or after an inspection has been schedules subsequently requests a later date without reasonable explanations. In addition, delays can occur when a company fails to respond to FDA attempts to schedule an inspection.

Delaying In – Progress Inspections

Which may result in drugs being deemed to be adulterated, may occur when a company will not allow access to specific areas of a facility to a future time and date, or not disclosing the existence of facilities that are engaged in activities that can be inspected.

Thus, limiting the time available for inspection available for inspection. In a July 2013 warning letter2, Indian pharmaceutical company Wockhardt Limited was cited for delaying disclosure of the existence of an aseptic filling line for pre-filled syringes manufactured for export to the U.S. market.

Thus, preventing or delaying the direct observation of its operation. An additional scenario that may result in drugs being deemed to be adulterated, can occur when a company leaves an inspector in a conference room without access to the necessary resources to perform the inspection for an unreasonable period of time.

Delaying Production of Records and Documents

Which may result in drugs being deemed to be adulterated, can occur when a company does not provide requested documents, records or electronic files within a reasonable period of time. In the July 2013 warning letter, cited above Wockhardt Limited was cited for delaying an inspection when an inspector identified the presence of torn raw data records in a waste area and asked one of quality assurance (QA) Officer to remove these records for the investigator’s review.

The inspector was later presented with approximately 20 paper records, which did not include the records identified in the waste area earlier, and the QA Officer denied the presence of further records. However, when the inspector returned to the waste area and that the records were found to have been removed and placed in a different holding bag.

In addition, Wockhardt was cited for failing to produce records of quality control (QC) testing in a timely manner, when it failed to provide these records for three days, only producing them on the last day during the close out meeting.

Thus, preventing the effective review of these documents. In addition, Wockhardt was also cited for initially denying the presence of unofficial batch manufacturing records (BMR), only confirming the presence of such records two days later after plant operators had stated that senior management had directed the use of unofficial BMR and had regularly reviewed such documents.

Denying Inspections

Denying inspections includes active behaviors that prevent an inspector from commencing or completing an inspection and includes statements or actions that are intended to avoid an inspection or to deceive, mislead or mislead an inspector.

In July 2013, German healthcare company Fresenius Kabi was issued a warning letter3 following an inspection of its pharmaceutical manufacturing facility in India. During the inspection an QC employee denied several times performing any HPLC injections other than those reported in the QC testing records, and an employee was observed attempting to hide manufacturing records from the inspector in his pocket.

In addition, HPLCs and computers were removed from the facility for the duration of the inspection to conceal data manipulations. Later in the inspection raw data was found being stored in several folders on PCs despite the inspector being told that all electronic raw data files are automatically stored on a central server that is inaccessible by QC staff, and that no data would be found on computers associated with laboratory instruments.

Other examples of activities that may constitute denying an inspection, that may result in drugs being deemed to be adulterated, without reasonable explanation include:

• • Rejecting attempts to schedule and inspection
  • Not allowing an inspector to commence an inspection when onsite
  • Not allowing an inspector to inspect the facility because certain members of staff are not on site
  • Falsely claiming the facility does not perform regulated operations

Discontinuing operations for the duration of the inspection or part of the inspection.

• This might include such practices as all staff leaving to have a lunch or coffee break when an inspector visits a particular manufacturing area or laboratory

Limiting Inspections

Limitations of inspections, that may result in drugs being deemed to be adulterated, can occur when an inspector is prevented from conducting an inspection to the extent required under the law, without reasonable explanation. Some examples of actions that may constitute limiting an inspection are discussed below.

Limiting access to manufacturing facilities and process can occur if, without a reasonable explanation:

• A facility discontinues manufacturing for the duration of the inspection
• A facility limits direct observation of manufacturing processes, in whole or in part, to an unreasonably short amount of time, thus preventing an inspection of the facility as is usual and customary
• A facility limits direct observation of portions of the manufacturing process
• A facility unreasonably restricts access to particular areas of the facility
• A facility causes the investigator to leave the premises before the inspection is completed

Limiting photography is a controversial topic, particularly as all photographs taken during an inspection can subsequently be made publically available under the Freedom of Information Act. The FDA’s position is that photographs are an integral part of an inspection as they present an objective and contemporaneous representation of conditions prevailing in a facility.

FDA Inspectors

Despite a lack of any statutory authority to take photographs during an inspection, FDA inspectors are instructed not to seek permission from management before taking any photographs, but to advise management that photographs are an integral part of the inspection. In December 2014 Quality Liquid Feeds Inc. was issued a warning letter4 for refusing to allow an inspector to take photographs documenting evidence of CGMP violations.

Limiting access to records can also occur when a company without a reasonable explanation:

• Refuses to allow the inspector to review records he has the authority to inspect
• Provides some but not all requested records
• Unreasonable redacts records
• Limits the examination of records to an unreasonable short period of time by not providing records in a timely manner

Wockhardt Ltd

In July 2013 Wockhardt Ltd was cited for limiting the ability an inspector to review and analyse documents relating to QC testing, after failing to present documentation for QC testing of tablets for three days, despite repeated requests, only providing the data, to the inspector, during the close-out meeting at the end of the inspection.

In December 2015 the Zhejiang Hisun Pharmaceutical Company was cited for limiting the availability of records5. When, during an inspection, an analyst removed a USB thumb drive from a computer controlling an HPLC. When the inspector asked for the drive, the analyst instead left the room with the thumb drive.

Management provided the inspector with, what they asserted was, the thumb drive in question approximately fifteen minutes later. As it was impossible to know whether management provided the same drive, that the analyst had removed this company deemed to have not provided records in a timely manner.

Fresenius Kabi Oncology

Refusing to permit an inspection includes both active and passive activity that prevents an inspection from proceeding. This can include failing to perform necessary actions to allow the inspection to take place, such as not unlocking doors to specific areas or not allowing the inspector to enter the site.

As an example, during an inspection at Fresenius Kabi Oncology Ltd in India, foreign material was observed inside an area. However, a request to open the area was delayed until a knowledgeable person became available. When the inspector later returned to the area, it had been cleaned.

This company claimed that no material was present and that what appeared to be foreign material was a reflection of the light. However, the next day the inspector found a deviation report documenting the presence of the foreign material, together with a written instruction to clean the equipment.

Coming in Part 2

In part 2 of this article released next week we will be discussing actions a company can take to avoid obstructing an inspection.