FDA 483s due to Deficiencies in the Stability Program: Evaluation of Fiscal Year 2024

Observations made by the inspector during an FDA inspection are listed on the FDA Form 483. Spreadsheets summarizing the areas of regulation cited on FDA's system-generated 483s are available by fiscal year on the FDA's homepage in the subsection on "Inspection Observations". These spreadsheets represent the area of regulation and the number of times it was cited as an observation on a Form FDA 483.

Stability studies of pharmaceuticals are a well-established discipline and, of course, an important regulatory requirement. Nevertheless, as highlighted in previous articles, deficiencies in the stability program have been frequently cited in numerous FDA 483s over recent years.

The FDA has now published the data for the fiscal year 2024 (October 2023 – September 2024). As in previous years, we have again performed an evaluation with regard to deficiencies in the stability program.

Evaluation

In the area of "Drugs", the following number of reports have been issued in the past years:

Fiscal year 2019: 779 FDA 483 forms

Fiscal year 2020: 349 FDA 483 forms

Fiscal year 2021: 215 FDA 483 forms

Fiscal year 2022: 466 FDA 483 forms

Fiscal year 2023: 510 FDA 483 forms

Fiscal year 2024: 561 FDA 483 forms

Requirements for stability studies and stability testing are defined in the Code of Federal Regulations, mainly in 21 CFR Part 211.166. In addition, stability testing is also mentioned in 21 CFR Part 211.194.

The following table gives an overview of typical deficiencies related to stability testing:

Reference Number Short Description Frequency (fiscal year 2019) Frequency (fiscal year 2020) Frequency (fiscal year 2021) Frequency (fiscal year 2022) Frequency (fiscal year 2023) Frequency (fiscal year 2024)

21 CFR 211.166(a) Lack of written stability program 67 18 15 30 18 47

21 CFR 211.166(a) Written program not followed 29 13 12 19 13 16

21 CFR 211.166(a) Results not used for expiration dates, storage cond. 10 4 2 6 6 

3

21 CFR 211.166(a)(1) Sample size - test intervals 4 1 0 3 5 2

21 CFR 211.166(a)(2) Stability sample storage conditions described 3 1 2 4 1 1

21 CFR 211.166(a)(3) Valid stability test methods 22 5 5 11 11 11

21 CFR 211.166(a)(4) Testing in same container - closure system 0 0 1 2 5 2

21 CFR 211.166(a)(5) Testing of reconstituted drugs 0 0 0 0 1 0

21 CFR 211.166(b) Adequate number of batches on stability 8 1 4 11 6 8

21 CFR 211.166(b) Accelerated stability studies 0 1 0 4 1 2

21 CFR 211.166(b) Tentative expiration date 1 1 0 0 0 1

21 CFR 211.166(c)(1) Homeopathic drugs, assessment of stability 3 2 1 1 2 3

21 CFR 211.166(c)(2) Homeopathic drugs, same container - closure 0 0 0 0 1 0

21 CFR 211.194(e) Stability testing records not included 0 0 0 1 0 0

Compared to the previous year, there has been a notable increase in cases where the absence of a written stability program was identified. In 47 cases, no documented testing program existed to evaluate the stability characteristics of drug products.

Looking at the ratio of 483s in stability relative to the total number of 483s in the area of Drugs, the percentage in fiscal year 2024 is three percentage points higher than in the previous year.

Fiscal year 2019 Fiscal year 2020 Fiscal year 2021 Fiscal year 2022 Fiscal year 2023 Fiscal year 2024

FDA 483 forms in total (Drugs) 

779

349 215 466 510 561

FDA 483 in the area of stability 147 47 42 92 70 96

Percentage 19% 13% 20% 20% 14% 17%

Conference Recommendations

How to keep Analytical Systems Current and Compliant

 25 November 2024, Technology Networks published a new article titled "The Museum of Analytical Antiquities," authored by Dr. Bob McDowall, a member of the ECA Analytical Quality Control Group (AQCG) Advisory Board, and Paul Smith.

The article begins with a critical observation: Many laboratories have "working analytical systems purchased back in the mists of time but have obsolete operating systems and/or instrument applications that have not been updated since initial qualification and validation." This reluctance to update stems from the misconception that revalidation is a costly and cumbersome process. Consequently, laboratories avoid software upgrades, leading to potential cybersecurity vulnerabilities and compliance issues.

Unlike physical instruments, software doesn't degrade over time. However, it requires regular updates to address, for example application enhancements, error and security fixes or outdated software. For instance, Microsoft’s planned discontinuation of support for Windows 10 in October 2025 highlights the urgency for laboratories to transition to Windows 11 or adopt more modern platforms. Ignoring such changes can leave systems vulnerable and non-compliant with evolving standards.

The article emphasizes the importance of staying current with software updates and modernizing laboratory systems. By doing so, organizations can ensure data integrity, regulatory compliance, and operational efficiency, while avoiding the "Museum of Analytical Antiquities" that hinder progress. Through a thoughtful discussion, McDowall and Smith advocate for a proactive approach, because "it is much easier to have small incremental upgrades which are easier to handle, rather than major projects if left too long."

Pilot Report on the Electronic Product Information (ePI)

Experience gained from creation of Electronic Product Information (ePI) during a pilot has recently been published in form of a report. The report outlines the outcomes of the pilot and derives learnings and recommendations that will inform the next steps towards introduction of ePI for EU medicines.

Background

The pilot, which involved EMA and the national authorities of Denmark (DKMA), Netherlands (MEB), Spain (AEMPS), and Sweden (MPA), together with industry, resulted in the publication of 23 ePIs from real regulatory procedures, of both centrally and nationally authorized medicines. The ePIs can be viewed at the Product Lifecycle Management (PLM) Portal.

The PI of a medicine includes its summary of product characteristics (SmPC), the labelling and the package leaflet (PL). These documents accompany every medicine authorized in the EU and explain how they should be prescribed and used. They can be found, often as a PDF document, on the websites of EU regulators, with a printed PL usually also provided in the medicine’s box.

The introduction of product information in an electronic format (ePI) compatible with digital platforms opens new possibilities for patients and healthcare professionals to access and interact with vital, up-to-date information about their medicines.

Patient access to the electronic Package Leaflet (ePL)

A pre-requisite for successful adoption of harmonized ePI across the EU will be robust systems in place ensuring that the patient can easily access the electronic package leaflet (ePL) for their medicine. This will involve the following:

Easy access to the ePL: A user-friendly solution, not requiring high levels of digital literacy, to link the patient from the medicine box in their hand to the ePL.

Availability of a printed copy of the package leaflet: Provision of a printed PL in case the patient prefers to read the information on a paper copy.  

Implementation

Following ePI implementation, it will continually improve in several directions, including but not limited to:

Extending the digital workflow Implementation towards a smoother and more coherent process of data management, including data capture, analysis, storage and dissemination.

Developing advanced PLM portal functionalities and new features.

Potentially widen the scope to incorporate future product types (e.g., parallel traded medicines, veterinary medicines).

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Constant reminders in Pharmaceutical Quality System

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Article written using AI technology 

What is constant reminder

A **constant reminder** refers to something that consistently keeps a particular idea, event, or feeling in someone's mind. This can be a physical object, like a wedding ring symbolizing commitment, or an ongoing situation that evokes specific thoughts or emotions. The term emphasizes the persistent nature of the reminder, making it an unceasing prompt to recall important aspects of life or experiences

Inl what situations constant reminders are helpful ?

Health Management: They help individuals remember to take medications or attend medical appointments, improving adherence to health regimens

Goal Achievement: Reminders can keep personal or professional goals in focus, motivating individuals to stay on track with their objectives

Daily Routines: They assist in establishing beneficial habits, such as exercising or maintaining a balanced diet, by prompting necessary actions at specific times

Emotional Support: Reminders from friends or mentors can reinforce positive behaviors and attitudes, serving as encouragement during challenging times

How to utilise constant reminders are standard operating procedure

To utilize constant reminders as part of standard operating procedures (SOPs), consider the following strategies:

Regular Training: Schedule ongoing training sessions to reinforce SOPs, ensuring employees are consistently reminded of procedures and their importance

Automated Alerts: Implement automated systems that send notifications for upcoming tasks or deadlines related to SOPs, helping maintain compliance

Review Cycles: Establish a structured review cycle for SOPs, with reminders for regular updates to keep procedures relevant and effective

Document Management Systems: Use software that tracks SOP adherence and sends reminders when updates are made or reviews are due

can I place banners in work area as constant reminders?

Yes, placing banners in the work area can serve as effective constant reminders. They reinforce safety protocols and procedures, keeping important information visible and top of mind for employees. Banners can enhance awareness, promote a safety culture, and contribute to compliance with regulations by clearly communicating essential safety messages12. Strategically positioning these banners in high-traffic areas ensures they capture attention, helping to reduce accidents and injuries in the workplace

Two new PICS Documents on Remote Assessments published

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Summary 

PIC/S has published two guidance documents for inspectors: "Guidance on Remote Assessments" (PI 056-1) and "Aide Memoire on Remote Assessments" (PI 057-1). These documents have been prepared by the PIC/S Working Group on Remote Assessment.

The Guidance document is intended to provide guidance on the approach and use of remote assessments including a hybrid inspection as inspection tools to establish consistency amongst Inspectorates. It discusses the logistics for conducting remote assessments, including necessary technical aspects.

PIC/S defines three types of remote assessments which vary depending on the level of interaction:

Summary

Fully Interactive Remote Assessment

Partially Interactive Remote Assessment

Desktop Assessment

and one combination type "Hybrid Inspection".

The Aide-Memoire document utilises best practices for performing an interactive remote assessment, including hybrid inspections to assist GMP inspectors in the life cycle process of remote assessments. The Aide-Memoire should also contribute to a harmonised approach for remote assessments between the different PIC/S Members and foster reliance. Like a checklist, it includes prompts and questions to guide users through these processes.

Batch Uniformity and Drug Product Integrity / Advanced Manufacturing Technologies US FDA

In early January 2025, the U.S. Food and Drug Administration (FDA) announced the availability of two new documents.

Considerations for Complying with 21 CFR 211.110

The FDA explains that "this guidance, when finalized, will describe considerations for complying with the requirements in 21 CFR 211.110 to ensure batch uniformity and drug product integrity. In addition, this guidance discusses related quality considerations for drug products that are manufactured using advanced manufacturing. It also discusses how manufacturers can incorporate process models into commercial manufacturing control strategies."

The seven-page document opens with a concise introduction. The guidance is applicable to the manufacture of human drug products, including biological products, as well as animal drug products. However, it does not cover the manufacture of active ingredients. The background chapter sets a link to the use of advanced manufacturing and the use of process models as a part of commercial manufacturing control strategies.

The two main sections are titled:

General considerations for in-process sampling and testing

Additional considerations for advanced manufacturing and process models

Key aspects include:

In-Process Sampling and Testing: Manufacturers are encouraged to develop scientific, risk-based strategies for sampling and testing at critical points in the manufacturing process. These steps ensure consistent product quality throughout production.

Advanced Technologies: The guidance supports the use of real-time quality monitoring, process analytical technologies (PAT), and continuous manufacturing systems to streamline operations and improve efficiency.

Control Strategies for Modern Manufacturing: The FDA emphasizes that while process models and advanced technologies are integral to modernization, they must be paired with in-process testing to ensure continued control and compliance.

Advanced Manufacturing Technologies Designation Program

The FDA has also announced the release of its final guidance for industry titled "Advanced Manufacturing Technologies Designation Program." This document finalizes the draft guidance of the same name, originally issued on 13 December 2023.

According to the FDA, "this guidance provides recommendations to persons and organizations interested in participating in FDA’s Advanced Manufacturing Technologies Designation Program, which facilitates the development of drugs manufactured using an AMT that has been designated as such under the program."

The 16-page document is organized into the following sections:

Introduction

Background

AMT designation requests

Benefits of AMT designation

Questions and answers

Key benefits of the AMT program include:

Early Engagement with FDA: Applicants gain access to early-stage discussions with FDA experts to address potential challenges in regulatory approval.

Expedited Assessments: The program accelerates the review and assessment process for applications involving AMT-designated technologies.

Improved Drug Supply and Quality: By integrating advanced control strategies, the program helps manufacturers meet demand for life-sustaining and critical medicines while minimizing quality risks.

The program highlights the importance of fostering innovation to enhance product quality and support the reliable availability of essential medications.

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Is Cloud Computing Open or Closed System according to 21 CFR Part 11?

The trend in the pharmaceutical industry is also moving towards cloud computing. Financial but also organizational advantages speak for the cloud. At the same time, however, potential dangers and regulatory restrictions should also be taken into account. Nine experts from the pharmaceutical industry and regulatory authorities answer a comprehensive catalog of questions from the following GxP-relevant topics:

Basics of Cloud Computing Technology

Regulations and Expectations of Inspectors

Customer-Supplier-Relationship

Requirements for Cloud Service Providers (CSP)

Requirements for Supplier Evaluation and Supplier Audits

Requirements for Qualification / Validation

The following question is one of a series of questions that we will publish in further GMP News articles on this site in the coming weeks.

Question 24: If the pharmaceutical user has data in the cloud, what type of system is it? Is this an open or closed system according to 21 CFR Part 11? - Basics of Cloud Computing Technology

This is easy to answer using the definition below, even if it is an "on-premise" application: "It is an open system". The cloud provider carries out the compliance checks. The pharmaceutical company can only introduce the corresponding controls via contracts and check them via audits. Therefore, direct control is not possible!

Definition 21 CFR Part 11 § 11.3:

(a) The definitions and interpretations of terms contained in section 201 of the act apply to those terms when used in this part.

(b) The following definitions of terms also apply to this part:

 - (4) Closed system means an environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system.

- (9) Open system means an environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.

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EDQM publishes new FAQ on System Suitability Test (SST)

The EDQM has announced the addition of a new FAQ to its existing series, addressing the system suitability test (selectivity) in chromatographic assay procedures. This update comes in response to user inquiries received via the HelpDesk.

The new FAQ specifically references the phrase, “as described in the test for related substances with the following modifications,” which appears in many monographs. The answer clarifies that in such assays, the SST is part of the analytical procedure. Consequently, "the reference solution prepared for the selectivity test, as part of the purity test, must be analysed in the assay even if this solution is not expressly mentioned under ‘ASSAY’."

In a press relase dated 17 December 2024, the EDQM writes: "This addition is expected to enhance the support to users by clarifying the SST requirements that apply to assays by chromatographic procedures when an analytical procedure similar to the related substances test is used."

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CMDh/EMA: Update of Appendix 1 for Nitrosamines

Latest update on 08.01.2025

The nitrosamine Q&A document 'Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products' of the EMA/CMDh contains three annexes (Appendix 1-3) in the current version of July 2024. These documents are published on the EMA website and can be viewed under 'Questions and Answers'.

Appendix 1 was compiled by the 'Non-clincal Working Party (NcWP)' and the information provided there for the acceptable intakes (AIs) is based on the 'Carcinogenic Potency Categorisation Approach (CPCA)'. InDecember 2024, new substances were added to Appendix 1, which consists of a tabular list of substances, and some existing entries in the list were updated. These are marked in red in the list of Acceptable Intakes (AIs) and are clearly recognisable. These include

New

N-nitroso-anabasine

N-nitroso-anatabine

N-nitroso-desmethyl-chlorphenamine

N-nitroso-desmethyl-eletriptan

N-nitroso-desmethyl-galantamine

N-nitroso-desmethyl-rizatriptan

N-nitroso-desmethyl-zolmitriptan

N-nitroso-ivacaftor

N-nitroso-nilotinib

N-nitroso-nornicotine

N-nitroso-nor-oxycodone

Updated

N-nitroso-bupropion

N-nitroso-ketamine

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FDA Expectations in Qualification

There is relatively little information on FDA requirements for equipment qualification. You can find guidance in the FDA Guidance for Industry General Principles and Practices: Process Validation on 'DQ', 'IQ' and 'OQ'. However, the terms 'DQ', 'IQ' and 'OQ' are not mentioned there. A footnote refers to the ASTM standard E2500. But what does the implementation look like in practice in companies? A current Warning Letter gives some clues. 

What is it about?

An over-the-counter (OTC) drug manufacturer is criticised under 21 CFR 211.113 for finding germs in water monitoring. This water was used to manufacture OTC drugs and to clean the equipment.

Among other things, the FDA criticised the inadequate qualification of the water system. It refers to installation and functional qualifications carried out by the manufacturer in 2019, whereby data collection was only completed three years later. However, the data was not analysed. Subsequently, the company presented a PQ to the FDA, but did not check all parameters in accordance with the pharmacopoeia specifications. The company's own specifications (test for the absence of gram-negative microorganisms) were also violated as part of the PQ. This is also described by the company in the PQ report that was sent to the FDA. The company committed to set up a new validation of the water system.

This is not enough for the FDA. It emphasises the importance of a water system and demands a solid design and effective operation, maintenance and monitoring of the system. It also requires:

• A comprehensive corrective action plan for the design, control and maintenance of the water system.  
• A report on the validation of the water system. This report should also include a summary of any improvements to the system design and the monitoring and maintenance programme. 
•  The total bacteria count limits used to monitor whether the system is producing water that is suitable for the intended uses for each of the OTC products. 
• A detailed risk assessment that addresses the potential impact of the inadequately qualified water system with respect to batches of drug products currently distributed in the U.S. or within the expiration date 
• An indication of the actions that will be required in response to the risk assessment, such as customer notifications and product recalls.

Conclusion: Although the qualification levels DQ, IQ, OQ, PQ are not named in the FDA Guidance for Industry: Process Validation General Principles and Practices, they are still present in the industry. The addressee of the Warning Letter performed IQ, OQ and PQ activities. The FDA additionally required consideration of the design of a water facility. Which is equivalent to a DQ.