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  • The ICH Q3C(R9) “Guideline for Residual Solvents” was revised using the ICH Minor Revision Procedure and reached Step 4 of the ICH Process on 24 January 2024.The document adopts a minor revision to section 3.4. concerning the consideration of solvent volatility for analytical methods.

    The Q3C ICH Guideline was finalised under Step 4 in July 1997 and provides recommendations on using of less toxic solvents in the manufacture of drug substances and dosage forms, as well as setting pharmaceutical limits for residual solvents (organic volatile impurities) in drug products.

    As part of the maintenance process, the Q3C Guideline incorporated the revision and inclusion of new Permitted Daily Exposure (PDE) levels as new toxicological data for solvents became available.

    In section 3.4 the guideline states that: “If only Class 3 solvents are present, a non-specific method such as loss on drying may be used, if the method is properly validated. The impact of solvent volatility on the test method should be considered in the validation.

    Validation of methods for residual solvents should conform to the current version of ICH guideline Q2 on Validation of Analytical Procedures”.

    SOURCES:

    ICH: News

  • FDA has published the draft guidance “Conducting Remote Regulatory Assessments Questions and Answers Draft Guidance for Industry” to describe the Agency’s current thinking on the use of remote regulatory assessments (RRAs). FDA has used RRAs to conduct surveillance, reduce risk, meet critical public health needs, and help maximize compliance of FDA-regulated products. This draft guidance provides answers to frequently asked questions about what RRAs are, when and why FDA may use them, and how FDA may conduct them, among others.

    The term “RRA”, as defined in the Question and Answers section, include activities for which the FDA may use different terminologies, such as “remote interactive evaluations” and “remote record reviews“. RRAs were mainly used to support submissions or applications assessments of FDA-regulated products and to reduce delays.

    In the presence of travel restrictions during the COVID-19 pandemic, FDA utilized RRAs to assess establishments and their compliance with applicable FDA requirements.

    Based on this experience, FDA has noted the value of RRAs and concluded that, under certain circumstances, they should be retained for some scenarios outside the COVID-19 pandemic for all types of FDA-regulated products.

    The Agency is also issuing this guidance to promote greater consistency in the way RRAs are conducted, explaining the processes for responding to an RRA request and outlining the factors to consider in assessing whether an establishment has responded timely and appropriately to a mandatory request.

    SOURCES:

    https://www.fda.gov/media/160173/download

  • on January 6, 2024, the Indian Ministry of Health notified the revision of GMP rules in accordance with Schedule M of the Drug and Cosmetic Regulation, with the aim of ensuring robust quality control for pharmaceutical and biopharmaceutical products.

    With this revision, the emphasis is placed on enhancing and updating the existing GMP framework to align with the global standards and international expectations, in particular those of the World Health Organization (WHO). The review was also driven by the rapid evolution of the manufacturing and quality domain and the need to keep pace with the latest technological advances.

    With the amendment, the term ‘Good Manufacturing Practices’ (GMP) has been replaced with “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products”.

    Some of the major changes introduced in the revised Schedule M include the introduction of a pharmaceutical quality system (PQS), quality risk management (QRM), product quality review (PQR), qualification and validation of equipment, and a computerised storage system for all drug products.

    The revised Schedule M has 13 parts which provide GMP guidelines for the specific requirements for manufacturing pharmaceutical drugs and also include five new categories of drugs that were not previously covered under the rules.

    The new categories include pharmaceutical products containing hazardous substances such as sex hormones, steroids (anabolic and androgenic), cytotoxic substances, biological products, radiopharmaceuticals, phytopharmaceuticals, and investigational pharmaceutical products for clinical trials for humans.

    The manufacturer must assume responsibility for the quality of pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the licence, and do not place patients at risk due to inadequate safety, quality, or efficacy. The manufacturer must also market a finished product only after getting satisfactory results from tests of the ingredients and retain enough samples of intermediate and final products to allow repeated testing or verification of a batch.” [Health Ministry notifies revised Pharma manufacturing rules under schedule M to ensure quality control – The Hindu].

    SOURCES:

    https://www.thehindu.com/

The U.S. Food and Drug Administration (FDA) has organized a stakeholder call to discuss the DSCSA implementation, which took place on 29 November 2023.

The Drug Supply Chain Security Act (DSCSA) drug supply chain security requirements, ten years after its implementation, are intended to improve the FDA’s ability to detect and remove potentially dangerous drugs, whether: counterfeit, stolen, contaminated or otherwise, from the supply chain.

Among the topics covered:

  • 10-year anniversary of DSCSA implementation
  • Stabilization period and expectations for trading partners to achieve interoperable, electronic tracing of products at the package level
  • Recent key guidances for industry related to supply chain security requirements
  • Looking ahead

Also in late November, the FDA announced that the CDER NextGen Portal (CDER NextGen) includes a DSCSA portal that enables the FDA and trading partners to communicate when the FDA requests information related to investigations of suspect or illegitimate products or during a recall.

The DSCA portal is used to:

  • Confirm basic information and points of contact for trading partners
  • Notify trading partners when they have messages from the FDA
  • Enable trading partners to respond to FDA messages and upload documents

Additionally, the DSCSA enables to:

On October 31st, the Swiss Medicines Inspectorate published a technical interpretation of GMP Annex 1. The interpretation focuses on some of the most significant changes of the revision 2022 of Annex 1 “Manufacture of Sterile Medicinal Products”. It also addresses aspects that were already included in the previous guideline version and have consistently prompted questions.

It should be noted that the document references the revised Annex 1 of the PIC/S GMP Guideline (PE 009) about the manufacture of sterile medicinal products. This was adopted on 9 September 2022 by the PIC/S Committee and came into force on 25 August 2023 (with the exception of point 8.123, which will become binding from 25 August 2024).

 

Contents of the document

The document consists of a list of questions regarding chapters of Annex 1 and the corresponding answers as interpreted by SwissMedic.

It includes the following sections:

 

  1. Purpose and scope
  2. Basics
  3. Definitions and abbreviations
  4. Interpretation: Questions and Answers

4.1     Scope (Annex 1, Chapter 1)

4.2     Premises (Annex 1, Chapter 4)

4.3     Utilities (Annex 1, Chapter 6)

4.4     Personnel/Training (Annex 1, Chapter 7)

4.5     Production and Specific Technologies (Annex 1, Chapter 8)

4.6     Environmental & Process monitoring (Annex 1, Chapter 9)

4.7     Quality Control (QC) (Annex 1, Chapter 10)

  1. Changes to the previous version

 

Some questions aim to provide further clarification on the language used in the document, but there are also several inquiries regarding the assessments of single-use systems (SUS).

The document contains a total of forty-six questions and their corresponding answers.

 

SOURCES:

Interpretation of GMP Annex 1 2022 (Rev. 1).

The ICH Q2(R2) Revised Guideline on Validation of Analytical Procedures” and the new ICH Q14 Guideline onAnalytical Procedure Development” were adopted by the ICH Assembly Regulatory Members during the Meeting on 31 October and 01 November 2023.

The proposed ICH Q2(R2) and ICH Q14 guidelines are intended to complement the ICH guidelines Q8 to Q12, as well as the ICH Q13 guideline for continuous manufacturing.

 

ICH Q2(R2)

ICH Q2(R2) presents elements included as part of registration applications. It provides guidance on selection and evaluation of the various validation tests for analytical procedures.

The comprehensive revision of the ICHQ2(R1) guideline was made to include more recent application of analytical procedures and to align the content with Q14 guideline.

The validation of an analytical method used for the assessment of the quality of drug substances and drug products, throughout entire life cycle was considered, describing considerations for the development of multivariate analytical procedures and for real time release testing (RTRT) or near infrared spectroscopy (NIR), which were not previously considered in the ICH Q2 guideline but are already used in practice.

Two annexes on the selection of validation tests based on the analytical method and with illustrative examples for analytical techniques have been added.

 

ICH Q14

ICH Q14 guideline aims to harmonise scientific approaches to analytical method development and describes the principles for their process description, change management and submission requirements for a minimal and extended approach. Applicants should be supported in not submitting analytical validation results in isolation but presenting them in the context of a performance evaluation against corresponding analytical development results.

The new guideline is intended to improve communication between industry and regulators and achieve a more efficient, science-based, and risk-based approval. This in turn should facilitate post-approval change management of analytical procedures.

 

SOURCES:

https://ich.org/pressrelease/press-release-ich-assembly-meeting-prague-czech-republic-octobernovember-2023

The European Medicines Agency (EMA) has updated the Questions and Answers on the outsourced activities chapter to include “Chains of Contracts” in the pharmaceutical industry, a “setup” where one or more parties (sites/companies) are acting as signatory in a chain of contracts that links them together.

This new setup represents an innovative approach that allows greater flexibility in contractual relationships between different entities involved in the production of medicines, while maintaining high quality and safety standards.

Therefore, the setup introduces one or several separate legal entities between the contract giver such as MAH and MIA holder responsible for QP certification of the product and the contract manufacturer or any other entities included in the manufacturing/supply chain as a contract acceptor. In fact, the GMP activities concerned are sub-contracted over one or several levels”.

 

Principles

The Questions and Answers clarifies in which exceptional cases such a “chain of contract” setup would be acceptable instead of direct written contracts, the conditions to be met are as follows:

  • robust and timely communication – It should be ensured that robust and timely communication between the MAH, the MIA holder responsible for QP certification and the contract manufacturers is secured through the “chain of contracts”.
  • Access to contracts – The MIA holder and the QP should have access to all of the contracts in the “chain of contracts”. Contract manufacturers should have access to those contracts relevant to the activities they perform and the associated responsibilities. As per EU GMP Chapter 4 all these contracts are to be considered as part of the Pharmaceutical Quality System.
  • Written assessment – The MIA holder and the QP should perform a written assessment of the suitability and functionality of such a setup.
  • Notification of changes – Any changes in the “chain of contracts” must be notified to and approved by the MIA holder and the QP prior to the change of the respective contracts being implemented.
  • Audited and evaluated according to EU-GMP standards – All parties involved in the “chain of contracts” setup should be audited and evaluated in accordance with Chapter 7 and Annex 16 of the EU-GMP and should also be reflected in the supply chain diagram.
  • PQR – All contracts within the “chain of contracts” setup are reviewed as part of the product quality review (PQR) process.

Nonostante l’introduzione di questa nuova configurazione, l’EMA ha sottolineato che i “contratti scritti diretti” rimangono ancora la preferenza principale. I contratti scritti diretti sono quelli firmati tra le parti coinvolte direttamente nell’esecuzione delle attività specificate e offrono maggiore chiarezza e trasparenza nel processo.

Despite the introduction of this new setup, EMA underlined that “direct written contracts” are still prefererred. Direct written contracts are those “signed between the parties, that actually perform the activities stated in the contract”.

SOURCES:

Guidance on good manufacturing practice and good distribution practice: Questions and answers

After the FDA had already published an initial discussion paper addressing Artificial Intelligence (AI) in the manufacturing of medicinal products, in early 2023, the EMA issued a draft reflection paper outlining the current thinking on the use of artificial intelligence (AI) to support the safe and effective development, regulation and use of human and veterinary medicines, on 19 July 2023.

This paper reflects on principles relevant to the application of AI and machine learning (ML) at any step of a medicines’ lifecycle, from drug discovery to the post-authorisation setting and reports the experience of the EMA in this context, in which scientific knowledge is rapidly evolving.

Recently the success of ChatGPT and related reporting have made the topic of Artificial Intelligence accessible to a wide audience.

 

General considerations

In general, it is mentioned that AI and ML, if used correctly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal products lifecycle.

A risk-based approach to the development, implementation and performance monitoring of AI and ML tools should enable developers to proactively define the risks to be managed during the life cycle of AI and ML tools.

AI and ML tools, when used properly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal product lifecycle. Section 5 of the document lists some guidelines and documents that may provide useful recommendations for implementing AI/ML applications.

It is essential to highlight that the marketing authorisation applicant or MAH is responsible for ensuring that the algorithms, models, datasets, etc. used are fit for purpose and meet ethical, technical, scientific and regulatory standards.

 

Content of the document

The document addresses the following topics:

  • AI in the lifecycle of medicinal products
    • Drug discovery
    • Non-clinical development
    • Clinical trials
    • Precision medicine
    • Product information
    • Manufacturing
    • Post-authorisation phase
  • Regulatory interactions
  • Technical aspects
    • Data acquisition and augmentation
    • Training, validation, and test data
    • Model development
    • Performance assessment
    • Interpretability and explainability
    • Model deployment
  • Governance
  • Data protection
  • Integrity aspects
  • Ethical aspects and trustworthy AI

 

Conclusion

The quickly developing field of AI and ML shows great promise for enhancing all phases of the medicinal product lifecycle.

Finally, the use of AI in the lifecycle of medicines should always comply with existing legal requirements, considering ethics and its underlying principles, and with due respect for fundamental rights. A human-centred approach should be adopted in the development and use of AI and ML.

SOURCES:

The Mutual Recognition Agreement (MRA) between Switzerland and the United States in Good Manufacturing Practice (GMP) for medicinal products has entered into force from 27 July 2023.

This agreement in principle establishes a mechanism whereby each country recognises GMP inspections carried out by the regulatory authority of the other, i.e. Swissmedic for Switzerland and the Food and Drug Administration (FDA) for the United States.

Both authorities are thus able to mutually use GMP inspections and their results in order to avoid duplicate inspections.

A significant aspect of this MRA is that it is not only limited to human medicines, but also includes veterinary medicines

In addition to the FDA and Swissmedic, the Office of the U.S. Trade Representative and the State Secretariat for Economic Affairs of Switzerland had also signed the agreement. These institutions play an important role in facilitating negotiations and cooperation between the two nations to ensure the proper implementation of the agreement.

The Mutual Recognition Agreement is based on the Food and Drug Administration Safety and Innovation Act, enacted in 2012, which allows the FDA to enter into agreements with other regulatory authorities to recognise inspections performed by them. This regulatory environment has created a favourable environment for international collaboration and mutual exchange of information.

SOURCES:

https://www.swissmedic.ch/swissmedic/en/home/news/mitteilungen/inkrafttreten-mra-swissmedic-fda.html

 

 

This guidance, published in March, is aimed at all those involved in the regulatory submission of medicinal product data. It supports the development and implementation of the International Organization for Standardization (ISO) Identification of Medicinal Products (IDMP) standards for substances, terminologies and other information used throughout the medicinal product development lifecycle worldwide.

The purpose of these standards is to make the international exchange of medicines information between stakeholders more accurate, complete, and consistent.

The five IDMP standards and corresponding technical specifications, were developed within the ISO network member organizations. The standards, originally published in 2012 by ISO, provide a framework (data models, terms, definitions, etc.) to uniquely identify and describe medicinal products with consistent documentation and terminologies to enable reliable exchange of product information between global regulators, manufacturers, suppliers, and distributors.

The FDA supports these standards for the identification and description of marketed non-investigational medicinal products, with the goal of harmonizing the standards for the international exchange of medicinal product data.

This guidance serves as a guidance document made available by the FDA and contains helpful but nonbinding recommendations.

SOURCES:

FDA Guidance “Identification of Medicinal Products – Implementation and Use“.