news Tag

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“.

In the issue of Pharmacopeial Forum PF 49(2) the proposed modification of the current version of the chapter USP <1031> The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants was published.

 

Proposed Revision of <1031>

The Packaging and Distribution Expert Committee (PDEC) proposes the following revisions to update and expand the scope of the current chapter:

  1. Change the title to “The Biocompatibility of Pharmaceutical Packaging Systems and Their Materials of Construction“.
  2. Expand the scope of the chapter to encompass plastic materials of construction and plastic and elastomeric components for pharmaceutical packaging/delivery systems and for packaging of combination products.
  3. Add an overview of the USP classification of plastics, which identified six different classes of plastics (Classes I–VI). A review of the utilization of the classification system found that typically only the most stringent category (Class VI) was used by suppliers of plastic materials of construction and components, and pharmaceutical manufacturers. This classification system has been replaced by the term “pharmaceutical grade polymeric materials“, which is defined as materials that are in compliance with specific in vitro tests.
  1. Include the following significant additions:
  • A risk-based approach to biocompatibility evaluation
  • Assessment of test methods
  • Chemical characterization as a key part of the overall safety assessment process
  • Biological reactivity test failure analysis
  • Overall biocompatibility evaluation
  1. Add sections for Glossary, Appendix, and References.

SOURCES:

The proposed USP General Chapter <1031> is available after registration to the Pharmacopeial Forum.

The EMA has published an overview of the recommendations for the use of herbal substances and/or preparations in the paediatric population as set out in the European Union herbal monographs. The document summarises the indications and possible limitations of use in children, based on the assessment of the Committee on Herbal Medicinal Product (HMPC).

The age range and use of herbal medicinal products within this special patient population, are topics often addressed by healthcare professionals. The purpose of this overview is to provide a summary of the information included in the monographs for ease of reference.

The list is divided into two groups of herbal medicinal products:

  • well-established use -WEU: demonstrated sufficient safety and efficacy data (may only be placed on the market after obtaining a marketing authorisation);
  • traditional use -TU- accepted based on sufficient safety data and plausible efficacy (can be marketed after being registered through simplified registration).

The list is derived from the information contained in the EU herbal monographs, as adopted, and can be consulted either by alphabetical order or according to therapeutic areas, for example, constipation, cough and cold, wye discomfort, gastrointestinal disorders, sleep disorders and temporary insomnia, etc.

For each substance the indications in the therapeutic area, possible herbal preparations referred in the monograph, dosage form and method of administration, Target population and Justification for limited use, for example in children, are listed in a tabular list.

SOURCES:

More detailed information is available in the EMA document European Union herbal monographs: Overview of recommendations for the uses of herbal medicinal products in the paediatric population.

To view all EU herbal monographs go to Herbal: European Union herbal monographs.

EU Directive 2001/83/EC describes in Article 52 that member states must ensure the fulfilment of the duties of Qualified Person (QP) either by administrative measures or by subjecting QPs to a code of professional conduct.

These requirements have been extracted from the relevant documents and are summarized in the Good Practice Guide “EQPA Code of Practice for QPs – Duties and Responsibilities for Qualified Persons in the EU” and is available publicly on the European QP Association website.

The new version 9.0 launched in January 2023 comprises a new chapter “Ethics for the Qualified Person – A Professional Code of Conduct” in addition to general revisions and a revised Annex 1 with the national requirements.

As the European QP Association (EQPA) is not aware of a Code of Conduct being published by any EU/EEA authorities, it was decided to develop such a code until an official version becomes available by the EU regulatory or National Competent Authorities (NCAs).

The new code is specifically intended to define and ensure the ethical dimension for QPs. It might also be used in informing other groups (e.g. senior management) of the specific duties of the QPs. It is further intended to become a reference to QPs and NCAs.

The following ethical duties of the QP have been identified:

  • Selflessness
  • Integrity
  • Objectivity
  • Responsibility
  • Transparency
  • Honesty
  • Leadership
  • Knowledge
  • Prevent professional misconduct
  • Rigour and Robustness

 

SOURCES:

EQPA Code of Practice for QPs – Duties and Responsibilities for Qualified Person