Cleaning Validation and FDA WL

SOPs on Cleaning Validation not followed

The FDA criticizes that the cleaning validation for non-dedicated equipment and its maintenance are not sufficient to be used for their intended purpose. This was actually acknowledged by the company's quality assurance personnel. Furthermore, standard operating procedures (SOPs) had not been followed.

It was criticized that the company had neither collected nor analysed rinse or swab samples, although this was laid down in the operating procedures. It was also pointed out that equipment was dirty and not well maintained. The FDA concluded that this presented a risk of cross-contamination.

The company's response is interesting. They admit to deficiencies in maintenance and sanitary conditions and are recalling all active ingredients that were shipped to the US. They also informed the FDA that they are initiating a "change control" to create a cleaning validation plan and to train personnel on the documentation of cleaning and equipment release.

However, the FDA responded very clearly in the Warning Letter: they want to see not just announcements, but the actual cleaning validation plan and the equipment maintenance plan.

Further demands by the FDA

Improvements to the cleaning validation program with special emphasis on worst-case scenarios for drug manufacturing. This includes the identification and assessment of worst-case scenarios for

Drugs with higher toxicities

Drugs with higher drug potencies

Drugs of lower solubility in their cleaning solvents

Drugs with characteristics that make them difficult to clean

Swabbing locations for areas that are most difficult to clean

Maximum hold times before cleaning

A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

A comprehensive evaluation of the facility's cleaning and maintenance program.

A CAPA plan to improve routine cleaning and maintenance.

Conclusion

Since it is not only the deficiencies in cleaning validation and equipment maintenance that are so significant, the FDA recommends hiring a GMP consultant.

FDA WL on Cleaning Validation

Warning Letter - Deficiencies in the Control of Raw and Starting Materials

The FDA has investigated the hi u need it ugtygsyjthz yubsybh fhgjeg bb manufacturiyng practices of Shantou Kangjie Daily Chemical Industry Co, Ltd (China) and found significant violations of Current Good Manufacturing Practice (CGMP). The FDA concludes that the company's manufacturing processes do not meet the legal Syyugg ysg by HR t🇺🇦🇺🇳🇹🇹🇺🇬tzu,ghehtasfy,ehzrtyytyz🪳🇹🇳🔆🌺🪳 requirements, which means that the manufactured products are considered adulterated. The company was therefore placed on the 66-40 import warning list in the USA.

1. Key points of the violations

1.1. Lack of identity verification of raw materials (21 CFR 211.84(d)(1)).

The company did not perform systematic identity verification for incoming raw materials used in drug product manufacturing.

Of particular concern is that the ethanol used is not tested for methanol impurities, which poses a serious health risk.

The FDA requires the company to conduct a comprehensive evaluation of all suppliers and materials and to ensure the identity, strength, quality and purity of all components used.

1.2. Failure to have an adequate quality control (QU) unit (21 CFR 211.22(a))

The company has not established a functioning quality control (QU) unit responsible for monitoring the quality of all manufacturing processes.

As a result, the inspection and approval of materials, packaging and finished products is inadequate.

The FDA calls for a comprehensive evaluation of quality control systems and a remediation plan to strengthen the QU with clearly defined responsibilities and authorities.

2. Recommended actions

Implement strict identity verification of all incoming raw materials.

Qualification and monitoring of suppliers and materials to ensure product safety.

Establish a functioning quality control unit with clear authority.

Engage an external, qualified CGMP consultant to comprehensively review and improve manufacturing practices.

Submit a detailed report to the FDA within 15 business days describing corrective actions taken and planned.

3. Consequences for failure to correct the violations

Continued import bans ont products from the affected manufacturing facility.

Rejection of new applicatifF it ttufons for drug approval by the FDA.

Possible further sanctions if appropriate corrections are not made.

No further Extension of GDP Certificates in 2025 by EMA

Background

During the COVID-19 pandemic, various exemptions were introduced for GDP inspections as well as for the validity and extension of GDP certificates. The aim was to ensure the supply of medicines despite the restrictions caused by the pandemic.

In December 2023, the GMP/GDP Inspectors Working Group (IWG) announced that the validity of GDP and GMP certificates that expired at the end of 2023 would be extended until 2024 or until the next on-site inspection, whichever occurred first.

No Further General Extension

In its latest announcement, the EMA clarifies that a general extension of GDP certificates will no longer be granted in 2025.

The following justification is given: "The working group took into account that national competent authorities (NCAs) had resumed regular on-site inspections. It also considered that NCAs are using other methods to gather compliance information, such as distant assessments and inspections that international partners carry out. These methods enabled decisions on certificate validity. They also helped reduce inspection backlogs, which are expected to be resolved in 2025."

However, in individual cases, the national authorities may decide on a case-by-case basis whether any additional extension to a GDP certificate is needed.

Questions regarding GDP certificates and their validity should be directed to the competent authority that issued the respective certificate

Guidance Documents on Variation Notifications Updated

On the website of the HMA (Heads of Medicines Agencies), under the heading "Variations", you will find the "Guidance Documents" relating to the updated "Variation Regulation" (Commission Delegated Regulation (EU) 2024/1701 of 11 March 2024 amending Regulation (EC) No 1234/2008 as regards the examination of variations to the terms of marketing authorizations for medicinal products for human use).

Amongst a large number of other documents, these include the so-called "Best Practice Guides (BPGs) for the Submission and Processing of Variations in the Mutual Recognition Procedure". These consist of 8 chapters, which were last updated in October 2024. Chapters 3 and 6 were revised again in January 2025:

Chapter 3: CMDh BPG for the Processing of Type IA Minor Variations (Notifications) in the Mutual Recognition Procedure

Updates have been made to subsection 1. Introduction and Annex II.

Chapter 6: CMDh BPG for the Processing of (Super-)Grouped Applications in the Mutual Recognition Procedure

Chapter 6 contains changes in the subsections 2. Application, 4. Validation of the application and 6. Finalisation of Procedures as well as in the appendices Annex I and Annex II.

New Guidance for Industry draft on AI by FDA

In January 2025, the U.S. Food and Drug Administration (FDA) published a draft Guidance for Industry and other interested parties entitled 'Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products'. This draft provides recommendations for 'sponsors' and other interested parties on the use of artificial intelligence (AI) to support regulatory decisions regarding the safety, efficacy or quality of medicinal products.

A key element of the draft is the introduction of a risk-based approach to assess the credibility of AI models. This approach is intended to help establish and assess confidence in the performance of an AI model for a specific context of use (COU). The guideline emphasises the importance of a clearly defined context of use for each AI model, as this forms the basis for the evaluation of the model.

The risk-based approach comprises seven steps:

Step 1: Define the question of interest.

Step 2: Define the context of use for the AI model.

Step 3: Assess of the AI model risk.

Step 4: Develop of a plan to establish AI model credibility within the context of use.

Step 5: Execute the plan.

Step 6: Document the results of the credibility assessment plan and discuss deviations from the plan.

Step 7: Determine the adequacy of the AI model for the content of use.

The guide also emphasises the importance of continuous monitoring and maintenance of AI models to ensure that they remain reliable throughout their use. This includes regularly assessing model performance and documenting any changes that could affect the model's output.

The FDA encourages sponsors to contact the agency early in the process to address questions about assessing the credibility of AI models or the use of AI in drug development. Public comments on this draft can be submitted until 7 April 2025 to ensure they are considered in the final development of the guidance.

Tyche Industries Ltd — February 06, 2025

Failure to record all quality-related activities at the time they are performed.

Your quality unit (QU) failed to ensure the integrity of CGMP records. For example, during the inspection, a member of your management stated that two of your operators admitted to falsifying temperature data for a drying oven that was not turned on during the manufacture of a (b)(4) batch, which later failed to meet the residual solvents specification. In addition, an Assistant Manager in Production, an Assistant Manager in Quality Assurance, and a Quality Control Manager admitted to participating in the preparation of a “backdated calculation sheet” that was given to our investigator.

Your documentation practices were not indicative of a facility that is in compliance with CGMP.

2. Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the APIs beyond the official or other established specifications.

FDA documented rust-like residues inside (b)(4) non-dedicated (b)(4) used in the production of (b)(4). In addition, FDA documented bare footprints inside another (b)(4) used in the production of (b)(4). Each (b)(4) was labeled that it had been cleaned and was ready for use.

Inadequately cleaned and maintained manufacturing equipment can lead to potential cross- contamination that could compromise your API’s quality and safety.

Your response is inadequate. You state that you reviewed the quality of the products manufactured in the impacted equipment since February 2024, but you do not describe how you conducted this review, nor the reason you limited your review to this timeframe. In addition, you do not adequately explain how you will prevent the failure to clean equipment after personnel enter inside it from recurring. Finally, you state that personnel entering inside equipment should “wear cloth shoe cover after removing shoe,” but failing to wear suitable clothing, including appropriate footwear, poses an unacceptable risk to the product.

In your response to this letter, provide:

Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

3. Failure to test the identity of each batch of incoming production material.

Your incoming raw material used to manufacture API intended for the U.S. market was not adequately tested. For example, you did not test the (b)(4) used as a raw material in the production of (b)(4) for identity.

Your response is inadequate. You state that you “initiated the activity” to test (b)(4) for identity. However, you do not address whether all other raw materials are tested for identity or how you will prevent this deviation from recurring with new raw materials.

In your response to this letter, provide:

A comprehensive, independent review of your material system to determine whether all suppliers of raw materials, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable raw materials, containers, and closures.

The chemical and microbiological quality control specifications you use to test and release each incoming batch of raw material for use in manufacturing.

A description of how you will test each raw material batch for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s certificates of analysis (COAs) instead of testing each raw material batch for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming raw material batch.

A summary of results obtained from testing all raw materials to evaluate the reliability of the COA from each raw material manufacturer. Include your standard operating procedure that describes this COA validation program.

A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

Data Integrity Remediation

Access WL here

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

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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)