FDA CY 2023 Shortage Report

The FDA has published its calendar year 2023 Shortage Report to Congress. Surprising no one, shortages continue to be an issue.

Section 5 is the fun part, highlighting continued efforts for QMM, collaboration with foreign regulatory bodies, and other activities.

FDA Reorganization

FDA’s Reorganization Approved for Establishing Unified Human Foods Program, New Model for Field Operations and Other Modernization Efforts

The FDA’s reorganization has been unveiled and will be implemented on October 1st. As a total wonk, this is exciting.

There are two major changes:

Forming a Human Food Program (HFP) to consolidate a preventive approach will not have much impact on me professionally, but I’m hoping that as a consumer, we see significant dividends from this refocus.
ORA is being renamed the Office of Inspections and Investigations (OII) and will focus on inspections, investigations, and imports as its core mission. If nothing else, this will make explaining the structure of the FDA a heck of a lot easier.

Everything else seems to be mostly a lot of shuffling of the deck chairs that will have little impact.

EMA GMP Plans for Regulation Updates

Like one does, I watch upcoming regulations like a hawk. Here are a few of the forthcoming GMP changes coming from the 3-year work plan for the Inspectors Working Group.

Document	Intended Changes	When	My Thoughts
GMP Guide: Chapter 4 (Documentation)	Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Annex 11 (Computerised Systems).	Q1 2026	An update is needed to align with current thinking. Data Integrity has advanced significantly in the last five years, and Chapter 4 could benefit from alignment with the PIC/S guidance.
GMP Guide: Annex 11 (Computerised Systems)	Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Chapter 4 (Documentation).	Q1 2026	A necessary update. Will be curious to see how it aligns with the FDA’s CSA approach (which isn’t really all that new). We pretty much know what will be in it from the concept paper. At least it will solidify this requirement for cloud systems “Regulated users should 26 have access to the complete documentation for validation and safe operation of a system and be able to present this during regulatory inspections, e.g. with the help of the service provider.”
Guidelines on GMP specific to ATMPS	Review the Guidelines in collaboration with CAT and the European Commission following the publication of a new regulation on standards of quality and safety for substances of human origin intended for human application and need to update legal references and definitions. Review the Guidelines in the light of new Annex 1 Manufacture of Sterile Medicinal Products and consider whether any updates are necessary.	Q4 2026	This is a fast area of change, and this update is called for. Aligning to Annex 1 is overdue.
GMP Guide: Annex 3 Manufacture of Radiopharmaceuticals	A review and update of the Annex to reflect current state of the art.	Q4 2026	I’ve never worked in radiopharmaceuticals. Maybe someday.
GMP Guide: Annex 15 Qualification and Validation	In the context of new technology in facilities, products and processes and following up on LLE recommendations, and extend the scope to APIs.	Q4 2025	LLE is the EMA’s lessons learnt report (LLE) on Nitrosamines. I’d love to see significant changes to finally align with ATSM E2500 and other recent challenges in validation.
GMP Guide: Annex 16 Certification by a Qualified Person and Batch Release	Following up on LLE recommendations.	Q4 2025	I’m not a massive fan of QPs as structured. Not expecting that to change.
GMP and Marketing Authorisation Holders	To revise the paper in line with recommendations from the Nitrosamines LLE, to strengthen guidance for MAHs in terms of having adequate quality agreement with manufactures.	Q4 2025	Anything to strengthen quality agreements is probably a good thing.

Anytime we see a major chapter update in the Eudralex Volume 4 is an exciting year, and the next few promise to be big. Maybe not Annex 1 big, but maybe the EMA and PIC/S will surprise us.

Leveraging Inspection Manuals for GMP Inspection Readiness

The various agency inspection manuals are critical tools for inspection readiness. I want to lay out where to find some of these manuals and then go deep into pre-approval inspections, focusing on data integrity.

European Medicines Agency

The European Medicines Agency (EMA) has established detailed procedures and work instructions for coordinating and conducting Good Clinical Practice (GCP), Good Manufacturing Practice (GMP), and pharmacovigilance inspections. Here are the key points regarding EMA’s inspection procedures:

GCP Inspection Procedures

EMA identifies applications for GCP inspections based on risk assessment criteria and exchanges information on shared applications with the FDA.
Inspections can be joint (conducted concurrently by EMA and FDA inspectors) or sequential (conducted separately by each agency).
EMA notifies the applicant/marketing authorization holder (MAH) and inspects sites about upcoming inspections through the IRIS industry portal instead of formal letters.
Applicants/MAHs must provide a signed statement accepting the inspection and granting direct access to documents and medical records.
Requested documents should be provided directly to inspectors in electronic format after consulting the reporting inspector.
After the inspection, EMA receives the draft inspection report, finalizes it with the inspectee’s responses, and publishes it in IRIS.

GMP Inspection Procedures

EMA coordinates GMP inspections based on risk assessment for marketing authorization applications, variations, and routine re-inspections.
Work instructions cover areas such as inspection announcement, fee calculation, product sampling/testing, and report circulation.

Pharmacovigilance Inspection Procedures

EMA has specific procedures for coordinating pharmacovigilance inspections and managing non-compliance notifications from MAHs.
Work instructions detail the inspection program creation, data entry in databases, and interactions with third-country inspectorates.

The EMA aims to harmonize inspection processes with the FDA and other regulatory bodies to streamline collaboration and information sharing while ensuring clinical trial subject protection and product quality.

FDA

The FDA Investigations Operations Manual (IOM) is the primary inspection manual used by FDA personnel when performing inspections and investigations.

The key points about the IOM are:

It provides comprehensive instructions, procedures, and policies for FDA investigators and inspectors to follow when conducting inspections, surveys, and investigations.
It covers inspectional activities for foods, drugs, medical devices, biologics, cosmetics, and other FDA-regulated products.
The manual details procedures for inspections of manufacturing facilities, sampling, import operations, recalls, consumer complaints, and other compliance activities.
It aims to ensure inspections are conducted consistently across FDA field offices and provide clear guidance to the industry on the FDA’s inspection approach.
The IOM is updated periodically to incorporate new laws, regulations, policies, and technological changes impacting FDA’s operations.
While not legally binding, the IOM represents the FDA’s current thinking and policies on inspections and investigations.

The FDA Investigations Operations Manual serves as the comprehensive inspection reference and procedure manual for FDA field staff carrying out the agency’s oversight and enforcement activities across all regulated product areas.

Pre-Approval Inspections

For new facilities, CPGM 7346.832, the FDA’s Compliance Program Guidance Manual for Pre-Approval Inspections (PAIs) of drug manufacturing facilities, is critical to spend time with. It outlines the objectives and procedures for FDA inspectors to evaluate a facility’s readiness for commercial manufacturing before approving a new drug application.

The key objectives of CPGM 7346.832 are:

Assess if the facility has a quality system capable of controlling commercial manufacturing operations.
Verify that the manufacturing processes, formulation, and analytical methods conform to the application details.
Audit raw data integrity to authenticate the data submitted in the application.
Evaluate the facility’s commitment to quality in pharmaceutical development (new objective added in 2022 revision).

The guidance instructs inspectors on evaluating the firm’s quality systems, process validation, data integrity, laboratory controls, change management, investigations, batch release procedures, and compliance with current Good Manufacturing Practices (cGMPs). It aims to ensure the facility can reliably produce the drug product described in the application.

Data Integrity

CPGM 7346.832 has specific requirements for data integrity audits during drug manufacturing facility pre-approval inspections (PAIs). Utilizing this document is an excellent way to evaluate your data integrity program.

The key points are:

Objective 3 of the guidance is “Data Integrity Audit”—auditing and verifying raw data associated with the product to authenticate the data submitted in the application.
Inspectors must audit the accuracy and completeness of data reported by the facility for the product. This involves verifying the factual integrity (data matches what was submitted) and contextual integrity (supporting data is complete).
Inspectors should examine raw data, such as chromatograms, analyst notebooks, electronic data, etc., and compare it to the summary data in the application’s Chemistry, Manufacturing, and Controls (CMC) section.
The data integrity audit should focus on finished product stability, dissolution, content uniformity, API impurities, etc.
Inspectors must identify any unreported relevant data, data falsification, improper invalidation of results, or unexplained data discrepancies.
Indications of data integrity issues include altered raw data, references to failing studies, discrepancies between samples, and missing records.

The data integrity audit aims to ensure the CMC data submitted to FDA is complete, reliable, and can be fully authenticated from the raw data at the manufacturing site. Robust data integrity is critical for the FDA to decide on the application’s approval.

FDA Revised MAPP Impact to Foreign Inspections

The FDA has updated its MAPP for staff, revising the “Understanding CDER’s Risk-Based Site Selection Model” (5014.1 Rev. 1). The update details how the FDA will prioritize inspections under the SSM and adds a risk factor for establishments in countries with a history of violations. This is a new risk factor for a region or entire country, whereas previously, mainly individual criteria such as site quality history, site type, and time since last inspection were used.

This is a fascinating addition, and I’d love to see the actual data on this risk factor. Anyone know if this can be FOIA’d? It would be interesting to see the difference between India and Mexico or even if they’ve subdivided the US.