Root Causes: Updates And Insights On Quality And Inspections

We are happy to launch a new newsletter, Root Causes: Updates and Insights on Quality and Inspections. The newsletter, which will come out roughly monthly, will discuss new developments in FDA inspections and enforcement, and its regulation of manufacturing and clinical trials. We will also discuss occasional developments from overseas regulators, such as in Europe, that affect the U.S. market.

Manufacturing and chemistry, manufacturing, and controls (CMC) issues remain at the center of the U.S. Food and Drug Administration’s (FDA) regulatory agenda this year. In recent months, FDA has pursued changes on multiple fronts — a proposed rule to address advanced manufacturing arrangements, new CMC commitments and inspection-related engagement through the user fee negotiations, among other developments. These developments reflect FDA’s focus on obtaining greater insights into the drug manufacturing supply chain, as well as streamlining and updating certain operations. This newsletter rounds up both recent and notable developments in the past few months that are worth a read for sponsors, manufacturers, and life sciences industry stakeholders.

• CMC and Inspection-Related Enhancements Proposed for the Prescription Drug User Fee Act (PDUFA) VIII Commitment Letter
• FDA Issued a Proposed Rule Regarding Registration and Listing for Distributed Manufacturing Establishments and Certain Foreign Entities
• FDA Advances Two Manufacturing-Related Proposed Rules
• FDA’s Upcoming Agency Reorganization — “Simple Reform” Unveiled
• FDA Emphasizes the Importance of Good Clinical Practices, and Reaffirms its Commitment to Human Subject Protections and “Gold Standard Science” in the Global Clinical Trial Landscape

CMC and Inspection-Related Enhancements Proposed for the Prescription Drug User Fee Act (PDUFA) VIII Commitment Letter

The next chapter of the PDUFA program is taking shape — FDA kicked off the public meeting for PDUFA VIII on September 16, 2026. One month prior, on August 14, 2026, FDA released the proposed PDUFA VIII Commitment Letter for public review and comment. This letter outlines the proposed user fee commitments that would govern the program for fiscal years 2028 through 2032. PDUFA VIII builds on the CMC enhancements and lessons learned under PDUFA VII, continuing FDA’s efforts to strengthen communication with sponsors throughout product development and application review. As part of this effort, FDA has proposed a risk-based lifecycle approach to identifying and resolving manufacturing facility deficiencies, intended to support the timely development and availability of new and innovative products.

CMC facility issues are critical to advancing a product through FDA review and success in commercialization. Manufacturing facility deficiencies can result in Complete Response Letters (CRLs) and additional review cycles. To help prevent or mitigate these issues, or foster early resolution, the proposed Commitment Letter offers a “CMC facility lifecycle program.” This program is grounded in new and enhanced engagement mechanisms between FDA and industry that may occur before, during, and after an application review cycle. The opportunity for sponsors and FDA to communicate about these issues in a formalized setting, represents a meaningful development in advancing resolution of outstanding facility issues and bringing products to market.

As part of this initiative, FDA aims to publish draft guidance by October 1, 2028 covering facility readiness ahead of pre-approval inspection (PAI) or pre-license inspection (PLI); best practices and timelines for meetings held before submission, after inspection, and after an approval action; as well as methods sponsors can use to self-assess facility readiness. 

The Commitment Letter also introduces several new meeting types with defined windows and procedures. For example, the CMC facility pre-submission meetings for New Drug Applications (NDAs) and Biologics License Applications (BLAs) may occur three to six months before an original NDA/BLA or supplement is filed. During this meeting, applicants can discuss the manufacturing supply chain, facility interdependencies, risk mitigation, and prior inspection history to help inform FDA’s risk-based facility evaluation approach. Similarly, post-PAI or post-PLI meetings are also available to original NDAs or BLAs applicants. This type of meeting would allow original applicants to discuss inspection findings and proposed corrective actions after FDA flags Form 483 observations that could lead to a CRL. If a CRL is ultimately issued following inspection deficiencies, applicants may utilize a Type A post-action meeting to address what must be resolved before approval. In addition, FDA commits to notifying applicants at least 60 days before — and no later than mid-review-cycle for — any planned facility inspection tied to an original application. To evaluate the program’s effectiveness, FDA intends to engage an independent third party to hold a public workshop by September 30, 2030 examining implementation and its impact on facility readiness and CRLs.

For a more detailed review of the PDUFA VIII Commitment Letter, please see our August 2026 Advisory.

FDA Issued a Proposed Rule Regarding Registration and Listing for Distributed Manufacturing Establishments and Certain Foreign Entities

On July 13, 2026, FDA published a proposed rule that would amend drug establishment registration and drug listing requirements for establishments engaged in distributed manufacturing (DM) and certain foreign drug establishments. The proposal would create a DM-specific registration pathway for eligible distributed manufacturing establishments (DMEs) operating under a hub-and-spoke model, allowing the hub and geographically dispersed manufacturing units to register as a single establishment rather than requiring each location to register separately. To qualify, DM units generally would need to remain equivalent in design and operation, manufacture the same drugs under the oversight of a single quality unit and unified pharmaceutical quality system, and satisfy other specified criteria. The proposal would also permit units to be added, relocated, or removed through a streamlined update process, while requiring advance notice to FDA of unit relocations. 

Separately, FDA proposed to align its regulations with amendments to the Federal Food, Drug, and Cosmetic (FD&C) Act made by the PREVENT Pandemics Act by clarifying that foreign establishments manufacturing drugs, including active pharmaceutical ingredients, that are ultimately imported or offered for import into the United States must register and list those drugs even if they undergo further manufacturing at another foreign establishment before entering the United States. FDA stated that the changes are intended to improve supply-chain visibility, provide a clearer picture of where and how drugs are manufactured, and reduce administrative burdens for innovative manufacturers. For a more detailed summary of the proposed rule, please refer to our July 2026 Advisory. The comment period for the proposed rule closed on September 11, 2026.

FDA Advances Two Manufacturing-Related Proposed Rules

FDA is planning additional rulemaking related to manufacturing. One is Amendments to 21 CFR Parts 210 and 211; Current Good Manufacturing Practices; Advanced Manufacturing, Distributed, and Point of Care Manufacturing, which would clarify the application of Current Good Manufacturing Practice (cGMP) regulations to advanced manufacturing technologies, including continuous manufacturing, distributed manufacturing, and point-of-care manufacturing. The proposal would clarify how manufacturers may use a science- and risk-based approach to CGMP compliance, including flexible approaches to defining batches, modern control strategies based on real-time monitoring and material traceability, and lifecycle-based validation and process verification. It would also clarify CGMP expectations for manufacturing drugs produced in small quantities, including drugs for rare diseases. Publication of the rule was targeted for July 2026, although these timeframes often slip; the rule could be forthcoming in the fall or winter. 

FDA also proposed Amendments to 21 CFR Parts 201, 314, and 601 to Promote Supply Chain Transparency in Human Drug Labeling; Identifying API and FDF Manufacturing Sites, which would require brand and generic pharmaceutical manufacturers to improve transparency of pharmaceutical manufacturing information. The amendments are intended to enhance FDA oversight of the drug supply chain. Similarly, this rulemaking was also targeted for a July 2026 publication timeframe, and could be released in the coming months. 

FDA’s Upcoming Agency Reorganization — “Simple Reform” Unveiled

FDA intends to reorganize the agency’s structure, effective October 1, 2026. FDA announced this initiative on July 29, 2026, in a Statement of Organization, Functions, and Delegations of Authority published in the Federal Register. FDA intends to centralize and enhance key functions across the agency to reduce redundancies, improve efficiency, and advance alignment. This reorganization is the Simple Reform initiative that FDA referenced in its 2027 budget request documents. 

As part of the reorganization, FDA will expand the scope of FDA’s Office of Operations, consolidating a range of agency-wide functions, including information governance, Freedom of Information Act operations, records and eDiscovery, and other administrative services. FDA will also establish new offices, including the Office of Mission Information Technology Services, Office of Health Advancement, and Office of National Health Security. 

Changes to the Office of Inspections and Investigations (OII) are also expected. For example, the Office of Inspectional Performance Optimization will replace the Office of Field Operations and Response, and will have a different internal structure. Although shifts to OII are forthcoming, this does not mean FDA is pursuing a return to a general inspectorate. FDA confirmed this in an August 2026 FDA Voices blog post and noted it is strengthening investigator training and readiness, including through more structured onboarding, standardized training modules, and cross-functional development opportunities to ensure that investigators can operate effectively across different product areas, when needed. FDA also used this post to highlight its “intensifying” use of unannounced foreign inspection to assess manufacturing quality, and its focus on establishing parity for foreign and domestic inspections. Still, Andrew Byrnes, director of Center for Biologics Evaluation and Research’s (CBER) Division of Gene Therapy 1, conveyed at the American Society of Gene and Cell Therapy’s 2026 Policy Summit on September 14, 2026, that “the goal behind [Simple Reform], as it applies to inspections, is to have a more agile inspection workforce that can be more generalist.” 

FDA Emphasizes the Importance of Good Clinical Practices, and Reaffirms its Commitment to Human Subject Protections and “Gold Standard Science” in the Global Clinical Trial Landscape

In an FDA Voices blog post dated September 2, 2026, FDA reaffirmed the importance of Good Clinical Practice (GCP) and its commitment to protecting human subjects and rigorous scientific standards. Consistent with the agency’s recent focus on the rise of foreign clinical trials and their attendant risks, FDA addressed issues associated with the globalization of modern clinical research, which has made oversight of foreign clinical trial sites more challenging. For example, some foreign sites have denied the agency access or conditioned inspections on agreements that would improperly restrict the scope or conduct of the inspection or require FDA to enter into agreements it cannot lawfully execute. To address these concerns, FDA intends to expand its Bioresearch Monitoring (BIMO) inspection program, including by increasing coverage of Phase 1 and other early-stage trials, updating the risk-based criteria used to select international sites for inspection, and increasing public transparency when inspection access is denied or restricted so that sponsors and patients can take that information into account in development and regulatory decision-making. FDA also intends to increase scrutiny of clinical studies and sites not conducted under an Investigational New Drug (IND) or Investigational Device Exemption (IDE), particularly in jurisdictions where conditions raise concerns regarding data integrity or the adequacy of informed consent.

© Arnold & Porter Kaye Scholer LLP 2026 All Rights Reserved. This Newsletter is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.