By Phil Crooker, Vice President - Technical, Regulatory & Access, Parexel
On August 19, FDA published the final guidance Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers. You can find a copy of the guidance here https://www.fda.gov/media/141312/download. The Federal Register announcement can be found here https://beta.regulations.gov/docket/FDA-2020-D-1136.
FDA has previously made several public statements about its ability to conduct inspections and FDA personnel have also made policy comments in various public forums. Now that this guidance has been published, here’s the gist of the critical points that FDA made, information that wasn’t discussed and steps industry can take to be prepared for the implementation of these policies.
FDA’s outlook on performing inspections.
- FDA intends to continue using other tools and approaches where possible for pre-approval inspections (PAI). These include:
- Requesting existing inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements.
- Requesting information from applicants.
- And requesting records and other information directly from facilities and other inspected entities.
- FDA is using its internal COVID-19 Advisory Rating system to determine what type of regulatory activity can take place in specific geographic areas.
- FDA is continuing to conduct only “mission-critical” inspections and resuming prioritized domestic inspections (including PAI and surveillance) on a case-by-case basis, when it is possible to do that safely.
- Before FDA can begin phased resumption of inspection activities, the criteria in the National Guidelines for Opening Up America Again must be met.
- Foreign pre-approval and for-cause inspection assignments that are not “mission-critical” remain temporarily postponed.
- Foreign pre-approval and for-cause inspection assignments that are “mission-critical” will still be considered for inspection on a case-by-case basis.
- Whether or not FDA considers an inspection to be “mission-critical” involves several factors related to the public health benefits of access to the product. The same factors are used for domestic and foreign sites and include but are not limited to:
- Breakthrough therapy (BTD) or regenerative medicine advanced therapy (RMAT) designation.
- Products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute.
- Both PAI and for-cause inspections can be considered “mission-critical.”
What about the impact of inspections on new and pending applications?
- FDA is using all available tools and sources of information to support regulatory decisions on applications that include sites affected by the agency’s ability to inspect due to COVID-19. These tools include:
- Evaluation of manufacturing facilities during the quality assessment of all applications.
- Reviewing a firm’s previous compliance history.
- Using information-sharing from trusted foreign regulatory partners through mutual recognition and confidentiality agreements.
- Requesting records in advance of, or in-lieu of, facility inspections.
- Voluntarily requesting information from applicants, facilities and sites.
- Applications will not automatically receive a complete response letter (CRL) if FDA cannot conduct an inspection.
- Decisions about applications will be determined using a totality of the evidence test, using all inspection and facility-related information available to FDA.
- FDA will determine whether an inspection is needed based on both a risk-benefit analysis of the product and all available information about the manufacturing facilities.
- If FDA determines that an inspection is necessary before approval of an application, then the agency will communicate this situation to the applicant and generally follow one of these scenarios:
- The FDA will issue a CRL when an inspection is needed and due to travel restrictions the inspection cannot be conducted before the action date.
- If there is not enough information to decide about whether an inspection is necessary, FDA may defer action on the application (by extending the action date) until an inspection can be completed.
What’s not discussed in the guidance.
- FDA personnel have previously stated that unless an investigator(s) can physically access a manufacturing facility, then an inspection cannot occur and records in-lieu of an inspection are not considered a functional equivalent of an inspection (see report from the Pink Sheet here - https://pink.pharmaintelligence.informa.com/PS142476/US-FDA-Invites-Warning-Letter-FollowUp-Inspection-Alternative-Proposals-As-Pandemic-Persists). The agency did not use the new guidance to clarify how it was interpreting what actions actually constitute performing an inspection and the rationale for its current interpretation of Sec. 704(A)(4) of the Food, Drug and Cosmetic Act (FDCA).
- The guidance mentions requesting and using information from trusted regulatory partners through mutual recognition and confidentiality agreements. The Medicines and Healthcare Regulatory Agency (MHRA) has been relying on remote inspections during CVOID-19 (see the report here - https://pink.pharmaintelligence.informa.com/PS142566/UK-MHRA-Relies-On-Remote-Drug-GMP-Inspections-As-COVID19-Pandemic-Grounds-Inspectors). FDA didn’t discuss how it would handle evaluating or using inspection reports from such trusted partners as MHRA that resulted from remote or desk-based audits of manufacturing facilities.
- No further details were given about the agency’s advisory rating system, unlike the factors involved in the site selection model (see the FDA Manual of Policy and Procedure here - https://www.fda.gov/media/116004/download) or the stage-gates in the National Guidelines for Opening Up America Again.
- No mention was made regarding drug shortage listings, drugs considered to be critical under the terms of the CARES Act or drugs identified by the Biomedical Advanced Research and Development Agency (BARDA) as critical in the factors for whether or not an inspection might be classified as “mission-critical.”
- There was no discussion of whether a surveillance inspection could fall under “mission-critical” status and no specific mention of for-cause inspections conducted as part of a Warning Letter follow-up and close-out process.
- There was no indication from the agency whether it was now including its progress on gathering and reviewing inspection and facility-related information as part of the PDUFA milestones for mid-cycle meetings and late-cycle meetings.
What can industry do to be prepared?
- Remain extraordinarily vigilant about product quality and CGMP compliance, even though FDA has been forced to postpone inspections. Even though its operations are limited now, the agency has begun its phased implementation of returning to pre-pandemic operations. Product quality and compliance need to be in place whether FDA is on your doorstep or not. Time and time again industry has been reminded that a quality culture is an essential part of any sustainable business.
- Take advantage of the opportunity to pressure-test your CGMP compliance and quality systems. Even if there are unanswered questions about what role remote or desk-top audits can play with FDA decision-making, use these tools to help assess your level of inspection readiness and also to facilitate inspections with international regulators who are relying on them (such as MHRA, Therapeutic Goods Administration and Health Canada). Having an acceptable inspection report can strengthen your facility’s compliance history but receiving a statement of noncompliance from a trusted foreign regulator can trigger adverse FDA action (such as import alerts and withhold recommendations for applications). Parexel® offers clients support for planning, executing and evaluating remote desk-top audits for CGMP compliance – for more information on our capabilities, visit https://regulatory-access.parexel.com/access-portal-assets/remote-desktop-cgmp-audits-factsheet or contact us.
- Discuss how to plan for the facility assessment and inspection process with FDA as soon as feasibly possible. FDA has indicated that it is open to receiving proposals from regulated industry – see the report here https://pink.pharmaintelligence.informa.com/PS142476/US-FDA-Invites-Warning-Letter-FollowUp-Inspection-Alternative-Proposals-As-Pandemic-Persists. Inspection plans and proposals can be submitted to FDA in a variety of ways and at different stages of product development and application review.
- Don’t forget that the agency will not just use manufacturing site information to determine whether or not an inspection is necessary but also the risk-benefit profile of the product and its regulatory status (such as expedited conditions for serious conditions, orphan indication). Ensure that your risk assessment or even mock summary basis of approval has been considered by FDA in its decision-making for whether to conduct an inspection or not.
- Some applicants with a diversified supply chain in their applications may have the capability to manufacture commercially from a site that FDA is fully capable of assessing and deciding whether an inspection is necessary or not. Consider your supply chain architecture for commercial readiness as soon as possible and evaluate whether your firm can spread the risk and minimize disruptions related to inspection decisions.
- The agency may send an applicant an “information request” letter or other “general correspondence” stating that an inspection cannot be performed due to travel restrictions and asking that the applicant acknowledge the agency’s position. Carefully review this correspondence and understand the effect of your acknowledgement and how that can be related to delayed action on an application or receiving a complete response letter. Use the opportunity to speak with the agency and understand how it reached the decision and what information was available and used in the assessment process.
How can Parexel help?
Parexel’s Regulatory & Access consulting organization includes 80+ former regulators from global agencies including the U.S. FDA, U.K.’s MHRA and NMPA in China and is exceptionally well placed to help mitigate risks of unnecessary delays by assisting with site selection, assessment of site-readiness, and to strategize about possible inspection waivers. Our remote desktop audit capabilities utilizes a five-point assessment process and a suite of virtual tools to allow for the evaluation of your facilities and capabilities, performance of SMEs interviews, and assessment of evidence of the implementation and control in order to make an informed evaluation of your site’s cGMP compliance.