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Update on Regulatory Guidance for Facility Inspections

The basic principle of pharmaceutical quality assurance is that a drug should be safe and effective for its intended use – and process validation plays a pivotal role in ensuring a drug’s quality.During the initial outbreak of the COVID-19 pandemic, travel and social distancing restrictions had a significant impact on regulatory inspections. In March of 2020, hands-off policies quickly became the new normal for both the US and the UK. Inspections, when not delayed altogether, were largely conducted via Zoom, via documentation or by other remote means in the months that followed.

While industry stakeholders and regulators alike stepped up to handle these challenges, pressure to resume on-site inspections grew steadily.

By August, both the FDA and MHRA released temporary interim guidelines for the industry that included resumption of on-site inspections. Here’s a quick rundown of eight common questions on where things stand today.

1. Have industry regulators gone back to business as usual?

The short answer is no. COVID-19 remains an ongoing global health emergency. Protecting the health of both pharma industry workers and inspectors alike is still a critical concern, as is the need to keep supply chains moving smoothly, minimize drug shortages, and ensure ongoing support for response efforts to the pandemic.

That being said, some travel restrictions have been relaxed, while precautions like personal protective equipment (PPE) and social distancing measures have been implemented across the industry. As a result, regulators in major markets like the US and the UK began reevaluating and prioritizing the resumption of activities that were delayed, reduced, or modified when the public health emergency was first declared –  including on-site inspections.

Many regulators have indicated their willingness to adopt flexible assessment submission strategies and practices, and some of the guidance that has been submitted is considered to be nonbinding recommendations rather than requirements. Yet many have also made statements reserving the right to enforce their authority if deemed necessary, as well as determining the priority of inspections and applications.

2. How are inspections being handled now?

Government agencies are working to resume their public health duties as much as possible, within the constraints of current government guidelines and while ensuring the safety of workers and inspectors. To help reduce risk, both the FDA and the MHRA will continue to perform many of the tasks typically associated with on-site inspections using other tools and approaches.

In the US, for example, the FDA may choose to handle pre-approval inspections by requesting existing inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements, requesting information from applicants, or requesting records and other information directly from facilities and other inspected entities. The MHRA is requesting as much documentation as possible in advance and has expressed its willingness to review information remotely where possible.

While regulators reserve the right to perform unannounced inspections, most domestic businesses that will receive on-site visits are being notified in advance for the foreseeable future. This process:

  • allows time for both parties to plan and coordinate aspects of the inspection (such as what information can be shared remotely).
  • helps to ensure safety by allowing businesses to provide the safest possible environment for the inspection
  • ensures that all appropriate staff members are present (in person or remotely) to assist the inspectors.

3. Are regulators taking local infection levels into account?

The FDA is using its COVID-19 Advisory Rating system to determine what types of regulatory activity can take place in any given region. Certain rating levels restrict its activities to “mission-critical” inspections.

A variety of factors determine what is deemed “mission-critical,” and these are evaluated on a case-by-case basis. Considerations include, but are not limited to, whether the products have received breakthrough therapy designation or regenerative medicine advanced therapy designation, or are products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute. Both for-cause and pre-approval inspections can be deemed mission-critical.

In safer geographic regions, the FDA has resumed prioritized domestic inspections, which generally include pre-approval and surveillance inspections.

In addition, the FDA has explicitly stated that it will continue to consider applications even if they reference a facility located in a region impacted by COVID-19 travel restrictions.

4. How should I prepare for an on-site inspection?

This will vary depending on your location, but be prepared to assume much of the responsibility for maintaining social distancing and other safety measures.

The MHRA, for example, encourages organizations to minimize the number of in-person staff present at opening and closing meetings or during facility tours. Inspectors may choose to conduct some meetings with subject matter experts and other personnel via videoconference, even if those personnel are in the same building.

If you anticipate any difficulties, be sure to discuss them with the inspection team ahead of time.

5. Is the FDA resuming foreign inspections?

As of this writing, foreign pre-approval and for-cause inspection assignments that aren’t considered mission-critical (defined by the same criteria as domestic inspections) remain temporarily postponed. Those deemed mission-critical may still be considered for inspection on a case-by-case basis.

6. How is the FDA ensuring the quality of imported products while inspections are limited?

For manufacturing facilities, the FDA is temporarily expanding the use of other tools and approaches, including:

  • Physical examinations of products arriving at U.S. borders
  • Product sampling and testing before release into commerce
  • Reviewing the compliance histories of facilities
  • Using information shared by trusted foreign regulatory partners through mutual recognition and confidentiality agreements
  • Requesting records directly from facilities “in advance of or in lieu of” certain drug inspections

If a product appears not to meet applicable standards for safety, effectiveness, or quality based on these approaches, the FDA has the authority to refuse admission of the product into the United States.

7. How are limited inspections affecting applications, especially if they include sites that can’t be inspected because of travel restrictions?

As with other inspection activities, regulators are exploring alternatives to determine whether an inspection is necessary and to support the application assessment. The FDA, for example, may consider a firm’s previous compliance history, use information sharing from trusted foreign regulatory partners through mutual recognition and confidentiality agreements, or request records “in advance of or in lieu of” facility inspections.

Applications will not automatically receive a complete response letter if the FDA can’t conduct an inspection. The FDA is informing applicants as soon as possible if an inspection is deemed necessary but can’t be conducted during the review cycle (e.g. because of travel restrictions). If there isn’t enough information to make a determination on the acceptability of a facility, the FDA may defer action on the application until an inspection can be completed.

8. Can a facility be added or changed in an FDA application if COVID-19 is causing supply chain disruptions?

Yes, but only if your drug application relates to the treatment or prevention of COVID-19, or to a drug on the FDA’s drug shortage list. In such cases, the cover letter to your submission should clearly state “Priority Review Requested” and include supporting information.

If you need to make manufacturing process or facility changes to address disruptions, you should refer to the agency’s most current guidance documents on making changes to an approved abbreviated new drug application (ANDA), new drug application (NDA), as well as scale-up and post-approval change guidance documents.

 

Because Neuland Labs serves pharma companies in the U.K, EU, and in the U.S., we stay up to date on regulatory changes throughout the world.

 

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