Vendor CoA based approval and FDA 483

Insufficient monitoring was carried out to ensure that the system was functioning properly and was suitable for production.

FDA requirements:

Validation of the system, including design, maintenance and continuous monitoring.

Implementation of programmes to monitor and record microbiological and chemical parameters.

Implementation of a risk assessment plan to evaluate the impact of system failures on the quality of drugs distributed in the US. This will include customer notifications and recalls as appropriate.

General measures:

The FDA requires the company to submit comprehensive corrective actions and timelines. These include

Detailed process validation programmes (PPQ) for active ingredients and finished drug products.

Systematic identification and control of process variability.

Monitoring and qualification of production facilities and equipment.

Risk assessment and preventive measures for products already on the market.

In addition, the company is expected to implement measures to ensure that all manufacturing processes comply with regulatory requirements and ensure the safety, quality and efficacy of the products.

API Testing is also relevant for the FDA - Warning letter to Indian Manufacturer

Access Letter HereThe system was poorly designed, e.g. with ‘blind spots’ and lack of continuous circulation, increasing the risk of biofilm formation.

Insufficient monitoring was carried out to ensure that the system was functioning properly and was suitable for production.

FDA requirements:

Validation of the system, including design, maintenance and continuous monitoring.

Implementation of programmes to monitor and record microbiological and chemical parameters.

Implementation of a risk assessment plan to evaluate the impact of system failures on the quality of drugs distributed in the US. This will include customer notifications and recalls as appropriate.

General measures:

The FDA requires the company to submit comprehensive corrective actions and timelines. These include

Detailed process validation programmes (PPQ) for active ingredients and finished drug products.

Systematic identification and control of process variability.

Monitoring and qualification of production facilities and equipment.

Risk assessment and preventive measures for products already on the market.

In addition, the company is expected to implement measures to ensure that all manufacturing processes comply with regulatory requirements and ensure the safety, quality and efficacy of the products. 

European Shortages Monitoring Platform (ESMP) goes live

The European Medicines Agency EMA announced that the European Shortages Monitoring Platform (ESMP) started with the full scope of functionalities on 29 January 2025 (which is ahead of the pre-defined deadline on the 2nd of February). All Marketing Authorisation Holders MAHs are obliged now to only use the platform to report data on medicine shortages and availability issues.

In addition to the routine shortage reporting by MAHs of centrally authorised products (CAPs), launched in November 2024, the full scope of functionalities of the ESMP is now available for crisis and MSSG-led preparedness reporting, for both MAHs and national competent authorities (NCAs). EMA collects data via the platform from national competent authorities (NCAs) and marketing authorisation holders (MAHs).MAHs and NCAs will be able to use these functionalities in the event of a public health emergency, major event, or MSSG-led preparedness activity.

The platform enables EMA to monitor the supply, demand and availability of medicines in three scenarios:

When preparing for and reacting to a crisis;

When EMA's Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG), also known as the Medicine Shortages Steering Group, requests this type of reporting

Under normal circumstances.

See the table below for more details on who reports what product type in which scenario:

Normal circumstances

Routine reporting of shortages of medicinal products.

Who needs to report:

Marketing authorisation holders

Product type:

Centrally authorised products

MSSG-led preparedness

Close monitoring of specific medicine(s) at the request of EMA's Medicine Shortages Steering Group (MSSG). The group creates a specific list of medicines for each action.

Who needs to report:

Marketing authorisation holders

National competent authorities

Product type:

Centrally authorised products

Nationally authorised products

Crisis

Reporting on supply, demand and availability of medicinal products during a public health emergency or major event. 

EMA publishes a list of critical medicines it monitors for each particular crisis.

Who needs to report:

Marketing authorisation holders

National competent authorities

Product type: 

Centrally authorised products

Nationally authorised products

Platform implementation

Full launch 

As of 2 February 2025, MAHs are obliged to use the platform to report data on medicine shortages of centrally authorised products in normal circumstances.

MAHs are also obliged to report data on supply and availability in the following situations:

For MSSG-led preparedness actions - MAHs must provide data on medicines that the Medicine Shortages Steering Group (MSSG) requested

During a crisis - MAHs must report data on centrally and nationally authorised medicines which are part of a list of critical medicines created for that specific crisis

As of 29 January 2025, national competent authorities (NCAs) can submit data in crises or MSSG-led preparedness actions related to:

national demand;

stock and supply levels;

patient estimations;

medicines usage.

To get an overview of the platform, including its scope, objectives and timeline for implementation, consult the informational brief available below:

European Shortages Monitoring Platform (ESMP) Informational brief

English (EN) (269.78 KB - PDF)

First published: 11/06/2024

View

For more information on EMA's role in addressing medicine shortages, see:

Crisis preparedness and management

Pre-launch for MAHs

As of 28 November 2024, marketing authorisation holders (MAHs) have the option to use the platform to report new shortages of centrally authorised products (CAPs).

Alternatively, for new CAP shortages, MAHs can still report using the regular process until 2 February 2025.

For shortages that have been reported to EMA before this transition period (28 November 2024 to 2 February 2025), MAHs should continue to use the regular process.

How to access platform

Marketing authorisation holders

As of 28 November 2024, marketing authorisation holders (MAHs) can access the platform and sign in via the link below:

European Shortages Monitoring Platform

MAHs need to have an active EMA user account and an ESMP industry user role to sign in.

A user guide is available for MAHs with related step-by-step instructions. They can find it in the platform and in the 'Guidance and training materials' section on this webpage.

More information is available for MAHs in the recorded training linked below:

European Shortages Monitoring Platform (ESMP) training session on routine shortage reporting for marketing authorisation holders of centrally authorised products (CAPs)

National competent authorities

As of 29 January 2025, national competent authorities (NCAs) can also sign in to report and monitor data in crisis and preparedness scenarios. 

NCAs can find step-by-step instructions on how to use the platform in the 'Guidance and training materials' section on this webpage.

A training course for NCAs who have access to the EU Network Training Centre (EU NTC) is available in the following link:

Link to EU NTC course for NCAs about the platform

Guidance and training materials

Guidance and training materials to support ESMP stakeholders in the adoption and use of the platform are available. 

EMA updates these documents on a regular basis and their content reflects the status at the time of publication.

To find high-level information on the platform, including how it works, reporting requirements for marketing authorisation holders (MAHs) and national competent authorities (NCAs), and how it can support EMA on human medicine shortages, see:

European Shortages Monitoring Platform (ESMP) essentials: Industry and network reporting requirements

English (EN) (1.49 MB - PDF)

First published: 31/07/2024

View

Training for MAHs and NCAs

EMA also publishes training materials directed to MAHs and NCAs. Select the expandable panels to access them.

Stakeholder engagement plan

An overview of all planned communication initiatives is available in the following document:

European Shortages Monitoring Platform (ESMP): Stakeholder engagement plan

English (EN) (243.77 KB - PDF)

First published: 31/07/2024

Last updated: 10/12/2024

View

The plan includes initiatives up to the first quarter of 2025. 

This is a living document and items may change to meet emerging needs. EMA confirms and communicates dates closer to each initiative. 

Events

Throughout 2024 and 2025, EMA will organise events to familiarise relevant stakeholders with the platform. 

Select the expandable panel below to find a list of event pages related to ESMP, including video recordings of past events.

EMA carries out public system demonstrations - or demos - to inform and involve stakeholders in the development of the European Shortages Monitoring Platform (ESMP).

Select the expandable panel below for information on how to access the related video recordings.

For information on other events featuring the ESMP, please search via keywords ('ESMP' or 'European shortages monitoring platform') in the events section on EMA's corporate website. There you can look for both upcoming and past events:

Events

Development and milestones of platform

EMA is developing the platform in line with the Scaled Agile Framework (SAFe).

Following an Agile approach means that the platform will start with basic features and EMA will gradually add more over time.

EMA will keep stakeholders up-to-date on the platform's development with informative sessions, technical guidance and public demonstrations.

For more information on SAFe at EMA, see: 

Network Portfolio: Agile transformation

The timeline below highlights the key ESMP-related developments and milestones, from the adoption of legislation requiring the platform to the availability of the first version of the platform. 

Development and milestones timeline

Adoption of Regulation (EU) 2022/123

First quarter of 2022

Registration of industry single point of contact (i-SPOC) for medicine supply and availability

Third quarter of 2022

For more information on iSPOCs, see Industry contact points for supply and availability of critical medicines.

IT developments and enhancements

From fourth quarter of 2022 to the first quarter of 2025

Interoperability with national and pharmaceutical industry systems

EMA is working to make the platform interoperable with national and pharmaceutical industry systems so that data can be easily exchanged between these systems.

This will help harmonise and simplify monitoring and reporting on medicine shortages in the EU.

While interoperability can reduce the need for user action, users will still be able to manually submit data through the ESMP interface.

An implementation timeline is available below. 

Implementation timeline

Definition of technical formats and implementation plan

First quarter of 2024

Detailing of data fields and formats, creation of guidance materials

Second and third quarter of 2024

Start of machine-to-machine solution implementation

Fourth quarter of 2024

Frequently asked questions

Marketing authorisation holders and national competent authorities can find answers to their most frequently asked questions in the document below:

Frequently asked questions on the European Shortages Monitoring Platform (ESMP)

English (EN) (288.68 KB - PDF)

First published: 31/07/2024

Last updated: 10/12/2024

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Contact

For more information and related questions, you can contact EMA through our AskEMA portal:

Send a question to the European Medicines Agency

Related documents

European Shortages Monitoring Platform (ESMP) release notes

English (EN) (284.74 KB - PDF)

First published: 28/11/2024

Last updated: 29/01/2025

View

Related content

Executive Steering Group on Shortages and Safety of Medicinal Products

Medicine Shortages Single Point of Contact (SPOC) Working Party

Crisis preparedness and management

Availability of medicines before and during crises

For Presentation on the Topic

ANVISA recognises CEPs

At the beginning of December, a news in the EDQM website newsroom informed that the Brazilian health authority ANVISA (Agência Nacional de Vigilância Sanitária) has started to recognise evaluation reports and documents from other authorities as part of its assessments. This includes, for example, the CEP of the EDQM, which can now be used when applying for the 'Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA)' and can therefore provide support when applying for medicinal products in Brazil.

Other authorities whose evaluations are now recognised are listed below:

European Medicines Agency (EMA) 

Health Canada 

World Health Organisation (WHO) 

Swissmedic 

UK Medicines and Healthcare products Regulatory Agency (MHRA) 

US Food and Drug Administration (FDA) 

Australian Therapeutic Goods Administration (TGA)

Elemental Impurities: Harmonized chapter finalized

In late November 2024, it was reported on the website of the EDQM (European Directorate for the Quality of Medicines & HealthCare) that the new harmonized chapter "Elemental Impurities (G-07)" of the "Pharmacopoeial Discussion Group (PDG)" had been signed in June 2024. The PDG consists of representatives from the European Pharmacopoeia (Ph. Eur.), the Indian Pharmacopoeia Commission (IPC), the Japanese Pharmacopoeia (JP) and the United States Pharmacopeia (USP).

In particular, the harmonization focused on the implementation of the updated requirements of the ICH Q3D guideline and the harmonization of analytical procedures. Special focus was placed on the following three points:

Sample preparation

Examples of suitable methods and detection techniques

Requirements for the validation of procedures

The new harmonized chapter "Elemental Impurities (G-07)" will be published in the regional pharmacopoeias according to the following timelines:

Ph. Eur: July 2025

USP: December 2025

JP: April 2026

IPC: July 2026

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).

Access Complete Information here

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.