The FDA announced in July (July 2020) that it planned to resume “prioritized” domestic inspections and later issued a Q&A document to further explain how it is now handling inspections of both domestic and foreign manufacturing facilities in the wake of COVID-19. What do pharma companies, CDMOs/CMOs, and other suppliers need to know?

Inside the FDA’s plan for resuming inspections

Earlier this year (March 2020), the US Food and Drug Administration (FDA) announced that it was postponing all domestic and foreign routine surveillance facility inspections due to the COVID-19 pandemic. Since then, beginning the week of July 20, 2020, the FDA began to work toward resuming prioritized domestic inspections using a COVID-19 Advisory Rating System. The system is being used to determine what categories of regulatory activity can take place in a given geographic region and, based on this determination, the FDA is either continuing, on a case-by-case basis, to conduct only “mission-critical” inspections, or, where possible to do so safely, resuming prioritized domestic inspections, which generally include pre-approval and surveillance inspections.

In considering what constitutes an inspection as “mission critical,” the FDA says it considers several factors that relate to the public health benefit of a given product. These factors 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. When determining whether to conduct a mission-critical inspection, the FDA says it takes into account concerns about the safety of its investigators, employees at a site or facility, and where applicable, clinical trial participants and other patients at investigator sites. The FDA says that it applies the same factors to both foreign and domestic facilities in determining whether to conduct an inspection.

Inspections of manufacturing facilities of drugs imported to the US

Given limited inspections, the FDA says that during this interim period of the COVID-19 pandemic, it is expanding the use of other tools and approaches, when possible, that have proven effective to help ensure the quality of drug products imported into the US. These tools may include the following: (1) physical examinations of products arriving at US borders or product sampling and testing before release into commerce; (2) reviewing the compliance histories of facilities, including using information shared by trusted foreign regulatory partners through mutual recognition and confidentiality agreements; and (3) 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 US. 

In addition to records requests, the FDA says it continues to work with US Customs and Border Protection to target products intended for importation into the US that violate applicable legal requirements for FDA-regulated products. The FDA has the ability through its Predictive Risk-based Evaluation for Dynamic Import Compliance Targeting (PREDICT) import-screening tool to focus its examinations and sample collections based on heightened concerns of specific products being entered into US commerce. The PREDICT screening has continued to adjust product risk scores as necessary throughout the COVID 19 outbreak.

Impact of limited inspection activity on drug applications

A crucial question for pharmaceutical companies and their suppliers is how the FDA’s limited inspection activity due to the COVID-19 pandemic is impacting drug applications. In its question-and-answer guidance issued last month (August 2020), the FDA says that it is “using all available tools and sources of information to support regulatory decisions on applications that include sites impacted by the FDA’s ability to inspect due to COVID-19. For example, the FDA says it will continue the quality assessment of all applications per normal assessment operations for all disciplines, where all manufacturing facilities will be evaluated using a risk-based approach consistent with existing guidelines. During this interim period, the FDA is using additional tools to determine the need for an inspection and to support the application assessment, such as reviewing a firm’s previous compliance history, using information sharing from trusted foreign regulatory partners through mutual recognition and confidentiality agreements, and requesting records “in advance of or in lieu of” facility inspections or voluntarily from facilities and sites.

The FDA says that the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Research and Evaluation (CBER) are continuing to evaluate applications strategically by applying a “holistic approach” in the decision-making process to determine if an inspection is warranted or if an inspection is no longer needed due to information gained through the use of the additional tools previously described. The FDA says it will continue to work directly with the applicants of those impacted and encourages applicants to be in communication with all their facilities and sites to ensure timely responses to any inquiries to support application assessment.

The FDA says that applications will not automatically receive a Complete Response Letter if it cannot conduct an inspection. The agency said that decisions regarding applications will be based on the totality of the information available to it, including the additional tools previously described. If, based on a benefit–risk assessment of the product and based on available information about the facility or site, it is determined that an inspection is needed before approval of the application, the FDA would communicate this to the applicant and would generally follow one of the several pathways as outlined below.

A facility/site raises concerns. If the FDA determines that an inspection is necessary for approval because available information raises concerns about the adequacy of the facility or site, and the inspection cannot be completed during the review cycle, the FDA says it will inform the applicant of this issue as soon as possible during the review cycle. Specifically, the FDA intends to inform the applicant that an inspection will be needed before the application can be approved, but due to restrictions on travel, the inspection may not be conducted before the agency’s action date. If the inspection of a facility that raises such concerns has not been completed by the agency’s action date, the FDA generally intends to issue a Complete Response Letter.

Insufficient information about a facility/site. If there is inadequate information to make a determination on the acceptability of a facility, the FDA says it may defer action on the application until an inspection can be completed. In such cases, the project manager will contact the applicant.

Manufacturing and supply-chain change requests

In its Q&A document, the FDA provided answers to common queries related to changes in manufacturing facilities for approved pharmaceutical products as outlined below.

Adding or changing a facility in response to a COVID-19 supply-chain disruption. If a drug application or biologics license application (BLA) relates to the treatment or prevention of COVID-19 or to a drug that is on FDA’s drug shortage list, the FDA says that the cover letter to the FDA should clearly state “Priority Review Requested” and include supporting information and/or follow procedures for notification of drugs in shortage. The FDA says it intends to continue following the procedures outlined in relevant Manuals of Policies and Procedures (MAPPs) and Standard Operating Procedures and Policies (SOPPs).

Data needed to support manufacturing process or facility changes from COVID-19-related disruptions. The FDA says that its existing guidance documents relating to making changes to an approved abbreviated new drug application (ANDA), new drug application (NDA), or BLA, as well as scale-up and post-approval change guidance documents for specific dosage forms should be applied when making a request to support manufacturing process or facility changes that arose due to the COVID-19 pandemic. If the circumstances resulting from the COVID-19 pandemic warrant atypical or flexible submission strategies, the FDA is advising the applicant to contact CDER or CBER as appropriate.

Accelerating the implementation of manufacturing changes during the COVID-19 pandemic. The FDA says it is using multiple tools to facilitate implementation of manufacturing changes, such as risk-based reduction in supplement reporting categories and flexible assessment practices, if manufacturing changes to an ANDA, NDA, or BLA need to be accelerated for drugs or biologics needed during the COVID-19 pandemic. Consistent with the FDA’s regulations for drug applications and BLAs related to post-approval CMC (chemistry, manufacturing, and controls) changes, the FDA may consider available information and approaches to mitigate the risk to product quality associated with the change to support a reporting category for certain supplements that is lower than would otherwise be most suitable (without the benefit of such information and risk-mitigation approaches). During this public health emergency, the FDA says it is willing to consider requests from applicants to submit certain changes using a lower reporting category based on such risk-mitigation information for drug applications or BLAs related to the treatment or prevention of COVID-19 or drugs/biologics in shortage. The FDA says it may additionally implement flexible assessment practices, such as expediting assessment of supplements, adjusting submission data requirements as part of a risk-benefit assessment, and using additional tools, when determining the need for inspections.

Travel restrictions in an area where a facility is located. The FDA says that an application with a facility in a region impacted by COVID-19-related travel restrictions does not preclude submission of the applicant to the FDA.