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.

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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.

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

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