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04 Oct

Posted at 16:21h in Blog

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

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04 Oct

Posted at 16:14h in Blog

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:

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04 Oct

Posted at 16:08h in Blog

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

 

 

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19 Jun

Posted at 15:13h in Blog

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“.

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19 Jun

Posted at 15:10h in Blog

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.

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19 Jun

Posted at 15:07h in Blog

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.

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31 Mar

Posted at 12:12h in Blog

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

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31 Mar

Posted at 12:03h in Blog

Compliance with Good Distribution Practice (GDP) by manufacturers and wholesale distributors is a key element in ensuring the quality and safety of medicinal products in the supply chain.

Possession of a manufacturing licence may include authorisation to distribute the medicinal products covered by the authorisation. Manufacturers performing any distribution activities consisting of procuring, holding, supplying, importing, or exporting medicinal products, should therefore comply with GDP.

PIC/S has developed an Aide Memoire “Aide-Memoire on the Inspection of Good Distribution Practice for Medicinal Products in the Supply Chain” (PI 044-1)”, which can be considered a good tool for improving the understanding and performance of inspectors and a “Questions & Answers (Q&A) document regarding the PIC/S GDP Guide” (PS/INF 22/2017).

These documents were drafted by the PIC/S Expert Circle on GDP and came into force on February 1, 2023.

The Aide-Memoire consists of ten tables containing general subjects and items to be investigated during the GDP inspection of manufacturers and wholesale distributors.

Some relevant references to the following PIC/S documentation are also included:

  • PICS Guide to Good Distribution Practice for medicinal products (PE 011- 1);
  • PIC/S Guide to GMP for medicinal products (PE 009-16 (Part I)).

 

SOURCES:

Aide-Memoire, Inspection of Good Distribution Practice (GDP) for medicinal products in the supply chain

Questions & Answers document regarding the PIC/S GDP Guide (PE 011-1)

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05 Jan

Posted at 14:59h in Blog

The current EU GMP Guidance Annex 11 “Computerised Systems” has been issued in 2011 and does not give sufficient guidance within several areas. There has been discussion for some time about revising this annex to meet current technological and regulatory developments. On 16 November 2022, the EMA (European Medicines Agency) published a “Concept-Paper on the revision of Annex 11 of the guidelines on Good Manufacturing Practice for medicinal products – Computerised Systems” that addresses the need to update Annex 11.

 

Proposed timetable until the publication of the new EU GMP Annex 11

  • Deadline for comments on the concept paper: 16 November 2023.
  • Publication and commenting of a draft of the new Annex 11: March 2025.
  • Approval and publication by the European Commission: June 2026.
  • Reasons for the revision of Annex 11.

 

Where is there a need for change and adaptation?

In 33 points, based on the structure and chapters of the current Annex 11, new points to be included and topics to be updated are presented.

Which topics should be included in the new Annex 11?

The following is an excerpt from the Concept Paper of some chapters in Annex 11 that have been identified as needing adaptation:

  1. Suppliers and Service Providers

The topic of cloud service providers should be addressed in particular:

  • [3,1] “For critical systems validated and/or operated by service providers (e.g. ‘cloud’ services), expectations should go beyond that “formal agreements must exist”. Regulated users should have access to the complete documentation for validation and safe operation of a system and be able to present this during regulatory inspections, e.g. with the help of the service provider.”
  1. Validation
  • [4.1] The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified. It should be emphasised that both activities consist of a verification of required and specified functionality as described in user requirements specifications (URS) or similar.
  • [4.1] Following a risk-based approach, system qualification and validation should especially challenge critical parts of systems which are used to make GMP decisions, parts which ensure product quality and data integrity and parts, which have been specifically designed or customised.

The topic of “agile methods” should be integrated here regarding deviations from previous classic development documents.

  • [4.5] It should be acknowledged and addressed that software development today very often follows agile development processes, and criteria for accepting such products and corresponding documentation, which may not consist of traditional documents, should be clarified.
  1. Audit Trails

Most of the new topics are mentioned here. What has been a very short chapter so far, topic should be described much more comprehensively in the new Annex 11. The points to be addressed include:

  • Audit trails must not be editable
  • Audit trails must not be able to be switched off for the “normal user” of a system.
  • Statements should be made about the frequency of audit trail reviews.
  • Audit trail data as GMP requirements are often created together with log data. It should be possible to be able to sort these data.
  1. Security

This topic should also be integrated more strongly under the aspect of external threats.

  • [12.1] The current section has only focus on restricting system access to authorised individuals; however, there are other important topics. In line with ISO 27001, a section on IT security should include a focus on system and data confidentiality, integrity and availability.

Security techniques, information security management systems and requirements are specifically mentioned here.

  • [12.1] The current version says that “Physical and/or logical controls should be in place to restrict access to computerised system to authorised persons”. However, it is necessary to be more specific and to name some of the expected controls, e.g. multi-factor authentication, firewalls, platform management, security patching, virus scanning and intrusion detection/prevention.
  • [12.1] It should be specified that authentication on critical systems should identify the regulated user with a high degree of certainty. Therefore, authentication only by means of a ‘pass card’ might not be sufficient, as it could have been dropped and later found by anyone.
  • [12.1] Two important expectations for allocation of system accesses should be added either here or elsewhere; i.e. ‘segregation of duties’, that day-to-day users of a system do not have admin rights, and the ‘least privilege principle’, that users of a system do not have higher access rights than what is necessary for their job function.

 

Conclusion

The current Annex 11 is partly superseded by technological and regulatory developments and that there is a corresponding need for adaptation.

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05 Jan

Posted at 14:54h in Blog

The latest version (version 16) of the “How to do” document – Interpretation of ICH Q7 Guide and “Review form” for active pharmaceutical ingredients was finalised in July 2022 and published on the new website of the APIC (Active Pharmaceutical Ingredients Committee) at the end of October.

The document aims to facilitate the implementation of the ICH Q7 guideline and provides recommendations on how it can be interpreted.

In this new version, the responsible task force of the APIC Quality Group, has made formal changes, additions and updates in the chapters (1) Introduction, (6) Documentation and Records, (10) Storage and Distribution and (12) Validation.

Following are some examples of relevant changes:

 

Chapter 6 Documentation and Records

This chapter has been thoroughly revised and contains many adjustments and innovations as well as formal changes. For example, in the first paragraph 6.1 “Documentation System and Specification” the acronym ALCOA has been replaced by ALCOA+, and more attention has been paid to electronic documentation and hybrid documentation systems.

In section 6.14, the sub-heading “Electronic systems” has been added; in sections 6.15, 6.16 and 6.17 have been almost completely reworded.

The following paragraphs have also been updated and revised:

  • 2 “Equipment Cleaning and Use Record”,
  • 3 “Records of Raw Materials, Intermediates, API Labelling and Packaging Materials”,
  • 4 “Master Production Instructions (Master Production and Control Records)”,
  • 5 “Batch Production Records (Batch Production and Control Records)”,
  • 6 “Laboratory Control Records”,
  • 7 “Batch Production Record Review”.

 

Chapter 10 Storage and Distribution

This chapter in the current version contains, in addition to formal changes, an adjustment in the second paragraph of section 10.11. All other steps in this chapter are left unchanged.

 

Chapter 12 Validation

In addition to numerous formal adjustments, this chapter has been fundamentally updated and reformulated.

In the first paragraph 12.1 “Validation Policy”, section 12.11 “Critical Parameters/Attributes General considerations” has been expanded to include the term Critical Quality Attribute (CQA) and its meaning has been described in detail.

In the same way, in paragraph 12.3 “Qualification” the term engineering has been added and in paragraph 12.8 “Validation of Analytical Methods” the sentence “The level of the validation required for in-process controls should be evaluated depending on the influence on the final API quality.” has been added.

Source: https://apic.cefic.org/wp-content/uploads/2022/03/ICH-Q7-How-To-Do-version16-final-version-published-on-24-oct-22.pdf

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