US FDA WL on Microbiology OOL

The company experienced seven out-of-limit (OOL) events for microbial content in a system used to generate a major component of drug products. Notably, at least two events showed microbial levels as high as 10,000 colony-forming units (CFU) per milliliter, far exceeding acceptable limits.

Despite the severity and frequency of these events, the company's investigations were deemed inadequate. The findings raise concerns about the company's ability to consistently produce components suitable for pharmaceutical use, with particular focus on "root cause determinations, corrective actions and preventive actions (CAPAs), and assessment of all potentially affected batches". Instead, the company limited its response to a narrow review of system test results from the day before and after each OOL event and relied on finished product test results to justify continued production-without demonstrating control over the system itself.

In the response to the observations, the company then indicated that "individual investigations with impact assessments will be created" for OOL results. Additionally, it was decided that the "quality lead will review and document results" on a defined basis. Furthermore, the company committed to train the quality team accordingly.

However, the FDA rates this response as "inadequate". The authority misses a "comprehensive retrospective risk assessment" and an evaluation of "the full scope and impact of OOL results". Also supporting documentation about the CAPAs was missing.

The FDA is now looking for an "independent assessment of the overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures" plus a "detailed action plan to remediate this system". The action plan should also include, "significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures".

This case underscores the importance of a thorough root cause determination and CAPAs, particularly when dealing with repeated events

Access Warning Letter here

ICH: New Guideline for Stabilities

The draft guideline "STABILITY TESTING OF DRUG SUBSTANCES AND DRUG PRODUCTS" of the ICH (INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE) was published in April 2025 and is now open for public comment. Comments are possible until the end of July 2025, with some exceptions specifically indicated on the ICH website.

This new version is intended to merge and replace the previous individual ICH guidelines (ICH Q1A-Q1F and ICH Q5C) in the area of stabilities. It will apply to active substances and finished drug products and takes into account new scientific and risk-based approaches and technologies. The table of contents can be summarised in the following points and annexes:

1 INTRODUCTION

2 DEVELOPMENT STABILITY STUDIES UNDER STRESS AND FORCED CONDITIONS

3 PROTOCOL DESIGN FOR FORMAL STABILITY STUDIES

4 SELECTION OF BATCHES

5 CONTAINER CLOSURE SYSTEM

6 TESTING FREQUENCY

7 STORAGE CONDITIONS

8 PHOTOSTABILITY

9 STABILITY CONSIDERATIONS FOR PROCESSING AND HOLDING TIMES FOR INTERMEDIATES

10 SHORT-TERM STORAGE CONDITIONS

11 IN-USE STABILITY

12 REFERENCE MATERIALS, NOVEL EXCIPIENTS AND ADJUVANTS

13 DATA EVALUATION

14 LABELLING

15 STABILITY CONSIDERATIONS FOR COMMITMENTS AND PRODUCT LIFECYCLE MANAGEMENT

16 GLOSSARY

17 REFERENCES

18 ANNEXES

ANNEX 1 REDUCED STABILITY PROTOCOL DESIGN

ANNEX 2 STABILITY MODELLING

ANNEX 3 STABILITY OF ADVANCED THERAPY MEDICINAL PRODUCTS (ATMPS)

Chapters 1, 2, 3, 4, 7, 8, 9, 11, 12, 13, 14 and 15 each have one or more detailed subsections.

The complete draft of the guideline "STABILITY TESTING OF DRUG SUBSTANCES AND DRUG PRODUCTS", the business plan and the concept paper as well as the work plan for this can be viewed on the ICH website under the "Public Consultations" tab. Under the "WG Presentation/Trainings" tab, you will also find instructions for commenting, which also contain a summary of the guideline.

Validation Master Plan and Validation Protocols Correlated

The FDA found that although there were requirements in the Validation Master Plan for process validation and hold times, no operating conditions such as bulk hold times, process limits or acceptance criteria for process parameters were specified in the validation protocol itself. 

In response, the inspected company submitted an updated validation protocol which, according to the FDA, still failed to address hold times and other details, such as information on sampling and the batch report that is used for the first validation batch. Subsequently, the FDA refers to its process validation guideline and describes the content of the guideline in a short section of the warning letter. 

Another point of criticism was the equipment. Contrary to the intended use, the circulation of the (water) system was stopped when it was not in operation. There was also a lack of monitoring of both chemical and microbiological parameters in accordance with the US Pharmacopoeia (USP). The response of the inspected company to operate the system permanently in the future is not sufficient. The entire system design is still to be assessed and monitoring introduced. In addition, the FDA requires interim measures and an investigation into the impact of the incorrectly validated system on product quality.

The FDA also expects a validation program, detailed PPQ plans, timelines for the PPQ, maintenance information, a description of monitoring and an assessment of the impact of defects on customer information and recalls.

Conclusion: Internal requirements in GMP documents must be implemented.

WHO: Updates on Method Transfer

In 2022, the WHO published the "Technical Report Series 1044, 2022" called "TRS 1044 - Annex 4: WHO guidelines on technology transfer in pharmaceutical manufacturing" on the subject of technology transfer. The previous document dates back to 2011 and has now been updated. 

The new annex consists of the following chapters and subsections and also lists an appendix 1:

Background

Abbreviations

1. Introduction

2. Scope

3. Glossary

4. Due diligence and gap analysis

5. Organization and management

6. Quality management and quality risk management

7. Documentation

8. Premises

9. Equipment and instruments

10. Qualification and validation

11. Life cycle approach

12. Phases of a technology transfer project 

       Phase I: Project initiation

       Phase II: Project planning

       Phase III: Project transfer execution

       Production (example: finished pharmaceutical product)

       Quality control: analytical procedure transfer

       Cleaning

       Phase IV: Project review and close-out

References

Appendix 1 Documentation commonly required for technology transfer

Chapter 12 "Phases of a technology transfer project" under "Quality control: analytical procedure transfer" and Appendix 1 deal specifically with the topic of method transfer.

Access guidelines here

Root Cause Analysis and FDA WL

Your firm failed to conduct adequate manufacturing investigations into out-of-specification (OOS) results obtained by your external laboratory for your (...), an over-the-counter (OTC) drug product. As such, root cause(s) for the OOS results were not determined and no corrective and preventive actions (CAPA) were identified."

"your cursory investigation lacked appropriate CAPA"

"As a manufacturer, you have a responsibility to fully investigate OOS results and process deviations that may impact product quality."

"the procedures for handling deviations and complaints are inadequate. For example, the deviations procedure lacks details for the investigation process".

FDA WL

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.