2024 FDA 483 Data

The FDA has published the 2024 Inspectional Observation Data Sets. I don’t think there are any surprise that on what the inspection observations data for fiscal year 2024 shows and what key GMP inspection themes emerge for drug manufacturers:

Quality Systems and Documentation

Inadequate Procedures and Documentation

Failure to establish or follow written procedures for various operations, including quality control, production, and process controls.
Lack of complete documentation for investigations, batch records, and laboratory testing.

Quality Control Unit Deficiencies

Inadequate responsibilities and authority of the quality control unit.
Failure to approve or reject components, products, procedures, or specifications.

Manufacturing and Process Controls

Equipment and Facility Issues

Inadequate design, maintenance, or cleaning of manufacturing equipment.
Deficiencies in facility maintenance, sanitation, and environmental controls.

Process Validation and Control

Lack of adequate process validation, especially for sterile drug products.
Insufficient control procedures to monitor and validate manufacturing processes.

Laboratory Controls

Inadequate Laboratory Practices

Failure to establish scientifically sound laboratory controls.
Deficiencies in test methods validation and stability testing programs.

Component Testing

Inadequate testing of drug components and reliance on supplier certificates without proper verification.

Sterile Drug Manufacturing

Aseptic Processing Deficiencies

Inadequate procedures and validation for sterile drug products.
Deficiencies in environmental monitoring and control systems for aseptic processing areas.

Training and Personnel

Inadequate Employee Training

Insufficient training of employees in GMP and specific job function.

Complaint Handling and Product Quality Reviews

Deficient Complaint Procedures

Inadequate procedures for handling product complaints.

Annual Product Quality Review

Failure to conduct adequate annual product quality reviews.

Equipment Related

Out of the 365 observations that mention equipment, 277 are from just 5 regulations. Let’s take a deeper look.

Reference Number	Short Description	Long Description	Frequency
21 CFR 211.63	Equipment Design, Size and Location	Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and maintenance]. Specifically, ***	85
21 CFR 211.67(a)	Cleaning / Sanitizing / Maintenance	Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, ***	76
21 CFR 211.67(b)	Written procedures not established/followed	Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, ***	60
21 CFR 211.68(a)	Calibration/Inspection/Checking not done	Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, ***	30

Improper design and qualification, improper cleaning, improper calibration and inspections. Yes these take work, but these are all areas that effort can improve.

Limiting and Delaying Inspections – Brands International as Example

I think many of us have been discussing the blatant obstruction demonstrated in the December 2024 Warning Letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection. Which it is important to remember congress has said is a big no-no.

I just want to stress that the Quality Manager there had a really bad day, week, month, year.

Good writeup of what to do around building your procedure for interviewing of employees during an inspection over at FDA Law blog.

FDA Inspections: Lesson 1 – Interviewing Employees

FDA Inspections – GAO Report

The GAO has published a report on FDA’s Inspections that found a 36% decrease compared to fiscal year 2019 in the number of inspections, partly due to reduced investigator capacity. A piece of information that should surprise noone.

The report highlights a concerning trend in the FDA’s drug inspection workforce. From November 2021 to June 2024, the vacancy rate among investigators who inspect foreign and domestic manufacturers increased from 9% to 16%.

I think we’ve all seen the impact of this. It’s worth spending a little time reading the report.

FDA Guidance on Delaying, Denying, Limiting, or Refusing Drug or Device Inspection

The FDA guidance “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection” published in June 2024 outlines the behaviors and circumstances that the FDA considers to be non-compliant with inspection requirements under section 501(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This guidance is essential for ensuring that drugs and devices are not deemed adulterated due to inspection-related issues.

The guidance aims to make sure transparency and compliance during FDA inspections to protect public health by ensuring that drugs and devices are manufactured by regulatory standards.

Legal Background

The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 added section 501(j) to the FD&C Act, which deems a drug adulterated if the owner, operator, or agent of a facility delays, denies, or limits an FDA inspection, or refuses to permit entry or inspection.

The FDA Reauthorization Act of 2017 extended these provisions to include medical devices.

Scope

The guidance applies to all facilities involved in the manufacture, processing, packing, or holding of drugs or devices. It defines what constitutes delaying, denying, limiting, or refusing an inspection, providing specific examples to illustrate these behaviors.

Examples of Non-Compliant Behaviors:

Delaying: Postponing an inspection without a reasonable explanation.
Denying: Explicitly refusing to allow an inspection to take place.
Limiting: Restricting the scope of an inspection, like limiting access to certain areas or records.
- I want to stress that this includes the situation where a facility provides some, but not all, records requested by the FDA investigator that FDA has authority to inspect. Everyone’s favorite delaying tactic.
- This also includes omitting or limiting the data contained in the electronic records when providing electronic copies of the records to FDA. This includes but is not limited to actions like removing data columns in Excel, removing data from the electronic record when providing the record to FDA, exporting data into reports without including all of the data fields (unless otherwise requested by FDA), or locking the electronic worksheet so that the data cannot be searched, sorted, or analyzed by FDA.
- Preventing an authorized representative of FDA from collecting statutorily authorized samples may be considered limiting the inspection. Examples of sample limitations include, but are not limited to, declining to allow or impeding FDA from collecting the following types of samples: environmental samples, finished product samples, raw material samples, in-process material samples, reserve samples in bioequivalence and bioanalytical studies, and labeling.
Refusing: Not allowing the FDA to enter the premises for inspection.

Background on FDA Guidance

The FDA issues guidance documents to communicate its current thinking on regulatory issues. These documents are not legally binding but give insight into how the FDA interprets and enforces laws and regulations. The guidance on delaying, denying, limiting, or refusing inspections was necessitated by the need to clearly define what constitutes non-compliance under section 501(j) of the FD&C Act. This clarity helps facilities understand their obligations and avoid actions that could lead to their products being deemed adulterated.

The guidance was finalized to replace the previous version issued in October 2014 and incorporates feedback and updates to reflect current practices and challenges in the inspection process. It is a critical tool for both the FDA and industry stakeholders to ensure that inspections are conducted smoothly and effectively, thereby safeguarding the quality and safety of drugs and devices available to the public.

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.