Review of Developments in GMP and the Regulation of Medicines June 2024
This month reported issues have come from the UK, EU, USA and WHO regulatory authorities.
The topics covered in this edition of the “Update” include:
UK MHRA
£85 million pledged to tackle antibiotic emergency
Topical steroids: introduction of new labelling and a reminder of the possibility of severe side effects, including Topical Steroid Withdrawal Reactions
MHRA’s AI regulatory strategy ensures patient safety and industry innovation into 2030
MHRA launches AI Airlock, its new regulatory sandbox for AI as a Medical Device (AIaMD).
Consultation on improved safety for high risk in vitro diagnostic devices
Consultation- Common specification requirements for in vitro diagnostic devices
Proposed framework for international recognition of medical devices
New cabotegravir formulations approved to help prevent HIV-1 infection in adults and adolescents
Pharmacists who illegally supplied more than 55 million doses of controlled drugs sentenced
EU
Multistakeholder workshop on shortages of Glucagon-Like Peptide-1 (GLP-1) receptor agonists
Real-world evidence
CAT quarterly highlights and approved ATMPs
Concept paper on revision of the guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling
Draft Guideline on stability testing for applications for variations to a marketing authorisation for veterinary medicinal products
Medical devices: new guidance for industry and notified bodies
One Health: a joint framework for action published by five EU agencies
Implementation of ISO standards for the identification of medicinal products (IDMP) in Europe
New recommendations for injectable veterinary medicines containing procaine benzylpenicillin
Information on the Member States requirement for the nomination of a pharmacovigilance (PhV) contact person at national level
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Draft guideline on ‘Content of the dossier for sterile substances’ released for public consultation
HPTLC fingerprinting in two monographs on homoeopathic preparations
Public consultation on a new general chapter on cell-based preparations for human use in Pharmeuropa 36.2
New European Pharmacopoeia Commission approach to gene therapy
Ireland HPRA
Applications for a Variation to a Manufacturer’s Authorisation
Combining Multiple Presentations of a Parenteral Product in One Product Authorisation
Guide to Attainment of Qualified Person Status in Ireland: Educational Requirements, Training and Licensing
Guide to Clinical Investigations Carried Out in Ireland
USA
REMS Logic Model: A framework to link program design with assessment
International
World Health Organisation (WHO)
WHO Technical report Series 1052, 2024
Products
First vaccine to protect adults from Chikungunya
Conferences
EDQM 4th Training Course on Quality Management for Tissue Establishments
European Shortages Monitoring Platform Essentials and Industry Reporting Requirements
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
£85 million pledged to tackle antibiotic emergency
Funding of £85 million will be announced at a global event to support the international community in tackling the growing threat of antimicrobial resistance.
The UK announces
up to £50 million to support countries and institutions in Africa in accessing essential antimicrobial drugs.
Additionally, up to £25 million which includes support to Caribbean countries and territories in strengthening surveillance systems for AMR.
A further £10 million to help establish an international scientific panel to coordinate global action
Topical steroids: introduction of new labelling and a reminder of the possibility of severe side effects, including Topical Steroid Withdrawal Reactions
Topical steroid products are safe and highly effective treatments for the management of a wide range of inflammatory skin diseases but have important risks, especially with prolonged use at high potency.
In the coming months, as a result of regulatory action, topical steroid products will be labelled with information on their potency to simplify advice for patients.
MHRA’s AI regulatory strategy ensures patient safety and industry innovation into 2030
The MHRA has set out its strategic approach to artificial intelligence (AI).
The MHRA was asked to provide a strategic, independent view of the agency’s approach to AI in the field of medicine and science and the steps the organisation is taking in line with the expectations set out in the Government white paper.
As a science-led organisation, the MHRA has a key role to play in enabling the achievement of the goal for the UK to be a science and technology superpower by 2030, and is considering the opportunities and risks of AI from three perspectives:
as a regulator of AI products
as a public service organisation delivering time-critical decisions
as an organisation that makes evidence-based decisions that impact on public and patient safety, where that evidence is often supplied by third parties
MHRA launches AI Airlock, its new regulatory sandbox for AI as a Medical Device (AIaMD).
Last month, the MHRA set out its strategic approach to AI in response to a white paper published in 2023 by Government.
This pilot project is a key part of that approach. It will help the Agency to identify and address the challenges for regulating standalone AI medical devices (AIaMD), initially seeking out and supporting 4-6 virtual or real-world projects through simulation. This will allow MHRA to test a range of regulatory issues for these devices when they are used for direct clinical purposes within the NHS.
The regulatory sandbox model is a recognised mechanism to help address novel regulatory challenges across sectors. The AI Airlock is a world-leading version in healthcare, designed to assist in safe development and deployment of AIaMDs, and this project will follow that robust process so manufacturers can deliver what is required to ensure the real-world viability of these devices.
Consultation on improved safety for high risk in vitro diagnostic devices
MHRA has launched a four-week consultation which will support improved safety for certain high risk in vitro diagnostic (IVD) devices. IVD devices are used to examine samples taken from the human body and to diagnose and monitor health conditions.
The consultation would require manufacturers to comply with additional measures for certain high risk IVDs, such as blood tests used to identify blood type before transfusions or tests which identify life-threatening diseases, introducing harmonised requirements for these products.
The MHRA intends to incorporate updates to IVD common specifications within a draft Statutory Instrument as part of the future core medical device regulations to be published later in 2024.
Consultation- Common specification requirements for in vitro diagnostic devices
MHRA is inviting members of the public, including the patients, medical device researchers, developers, manufacturers and suppliers, clinicians, other healthcare professionals to provide their views on the introduction of common specification requirements to the regulatory framework before IVD devices can be placed on the GB market.
Proposed framework for international recognition of medical devices
The MHRA’s statement of policy intent describes how the UK Government intends to recognise regulatory approvals from Australia, Canada, the European Union and the USA depending on device type, class, and prior approval. The MHRA continues to review the list of comparable regulator countries and is in active discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) to explore the recognition of medical device approvals from Japan.
The statement of policy intent focuses on ensuring safe access to quality-assured medical devices and reducing the duplication of assessments by comparable regulators to enable resource to be focused on more innovative products for the benefit of patient health.
This statement will also allow manufacturers to start considering whether their devices will be eligible for the proposed alternative routes to market.
New cabotegravir formulations approved to help prevent HIV-1 infection in adults and adolescents
The MHRA has authorised cabotegravir as 30 mg tablets and as a 600 mg long-acting injection administered every two months, to help prevent sexually transmitted HIV-1 infection in adults and adolescents weighing at least 35kg who are at an increased risk of infection.
Tablet-based PrEP is already available for those at risk. Cabotegravir would provide an alternative HIV prevention treatment option for eligible individuals should it be recommended by NICE. Cabotegravir 600 mg long-acting injection is the first injectable treatment approved to help prevent HIV-1 infection in the UK.
Both formulations of cabotegravir (tablets and long-acting injection) have been authorised by the MHRA for Great Britain under a national application procedure.
Pharmacists who illegally supplied more than 55 million doses of controlled drugs sentenced
Two pharmacists who sold ‘industrial’ quantities of Class C controlled drugs were sentenced to two years’ imprisonment each, suspended for 24 months, at Southwark Crown Court following an investigation by the Criminal Enforcement Unit of the MHRA. Having both pleaded guilty at an earlier hearing, Mandip Sidhu (47) of Littleover, Derby was sentenced to two years imprisonment on each of five counts of supplying Class C drugs and four months for forgery, all to run concurrently and suspended for 24 months on the condition that she completes 200 hours of community service for her role in the illegal supply of diazepam, zolpidem and zopiclone. Nabeil Nasr (42) of Cheadle, Greater Manchester, received a prison sentence of two years for each of two counts of supplying Class C drugs diazepam and zopiclone and one year for each of two counts of wholesale dealing without a wholesale licence, suspended for 24 months, also on the condition that he complete 200 hours community service.
The offences in both cases, which saw both Sidhu and Nasr illegally supplying Class C drugs on what was described in court as an ‘industrial scale’, took place between May 2013 and June 2017.
Both Sidhu and Nasr were pharmacists registered with the General Pharmaceutical Council at the time of offending; Sidhu the director of Pharmaceutical Health Limited (PHL), based in Derby, and Nasr owned several pharmacies across the North West of England.
The court heard that PHL, the company of which Sidhu was a director, purchased 4.27 million tablets in August 2014, and 4.5 million tablets in March 2015, even though PHL had not legally dispensed any medicines against a prescription since July 19, 2013.
For perspective, around 5 million diazepam tablets were legally dispensed against prescription in the whole of England during 2014.
These figures were dwarfed by the quantities of drugs passing through the hands of Sidhu and Nasr.
[Well done the MHRA for its perseverance over this matter. Were costs awarded against the individuals and was there recovery of profit from crime? MBH]
Europe
European Medicines Agency (EMA)
Multistakeholder workshop on shortages of Glucagon-Like Peptide-1 (GLP-1) receptor agonists
A shortage of medicines containing Glucagon-Like Peptide-1 (GLP-1) receptor agonists has been affecting EU Member States since 2022 and is expected to continue throughout 2024.
The shortage is due to an increased demand for these medicines in conjunction with other causes, such as manufacturing capacity constraints.
The medicines are authorised for the treatment of diabetes or for weight management under certain conditions or both. The off-label use for cosmetic weight loss and the emergence of falsified products further complicates the situation, particularly given the competing indications of these medicines.
EMA has established an Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) to play a central role in coordinating, preventing and mitigating medicine shortages in the EU.The MSSG has organised this multi-stakeholder workshop to bring together all relevant parties to facilitate a common understanding and to jointly discuss and identify possible additional solutions.
The objectives of this workshop are:-
clarify the needs and challenges of the different stakeholder groups in the context of shortages of GLP-1 receptor agonists,
share experiences of ongoing activities to mitigate and prevent shortages of GLP-1 receptor agonists,
identify novel solutions to mitigate and prevent the shortages of these medicines,
strengthen cooperation amongst all stakeholders and improve coordination of activities,
discuss and agree on key messages for communication and how to best reach target audiences.
Real-world evidence
EMA scientific guidelines on real-world evidence aim support the use of real-world data in regulatory decision-making.
CAT quarterly highlights and approved ATMPs
This report provides information on Advanced Therapy Medicinal Products (ATMPs) approvals and extension of indications of authorised ATMPs, as well as statistical data on product-related activities.
The period covered by this report is: February – April 2024.
Concept paper on revision of the guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling
The current guideline provides guidance on the integration processes of clinical and non-clinical data for the assessment of the risk of adverse maternal, fetal or child effects in humans, as well as effects on fertility. Further, there is guidance on how to communicate the potential or identified risk through the Summary of Product Characteristics (SmPC).
At time of marketing authorisation, often only non-clinical data is available to provide information on fertility, pregnancy and breastfeeding in the SmPC and PL.
The lack of clinical data on medicines safety for human fertility, during pregnancy and breastfeeding has long been highlighted as an area of public health need, and patients and healthcare professionals have expressed the need to have access to more information on the safety of medicines during pregnancy and breastfeeding.
The document is intended to provide updated guidance on the integration processes of clinical and non-clinical data for the assessment of the safety of medicines on fertility, in pregnancy and during breastfeeding.
Comment period ends 31 Aug 24
[A significant proposal of interest to many parties MBH]
Draft Guideline on stability testing for applications for variations to a marketing authorisation for veterinary medicinal products
This guideline replaces the existing Guideline on stability testing for applications for variations to a marketing authorisation for veterinary medicinal products.
Deadline for comment is 31 Aug 24
Medical devices: new guidance for industry and notified bodies
A new revision of the guidance available to applicants, marketing authorisation holders and notified bodies of medical devices has been published. This Q&A document provides practical considerations on the implementation of the medical devices and in vitro diagnostic regulations for combinations of medicinal products and medical devices.
The revision is based on the experience gained since the implementation of the new regulations and actual cases encountered. The guidance is provided to support the application of the regulations on medical devices and on in vitro diagnostic devices.
These two regulations changed the European legal structure for medical devices, introducing new responsibilities and requirements for EMA and national competent authorities in the assessment of certain categories of medical devices used in combination with medicines.
One Health: a joint framework for action published by five EU agencies
The European Centre for Disease Prevention and Control (ECDC), the European Chemicals Agency (ECHA), the European Environment Agency (EEA), the European Food Safety Authority (EFSA), and the European Medicines Agency (EMA) have published a joint framework for action to strengthen cooperation to support the implementation of the One Health agenda in the European Union (EU).
Implementation of ISO standards for the identification of medicinal products (IDMP) in Europe
Version 3 of Chapter 7: XEVMPD and SIAMED II to PMS – Initial migration guide has now been published
The EMA intends to migrate the Centrally Authorised Products (CAPs) and non-Centrally Authorised Products (non-CAPs) data held in the eXtended Eudravigilance Medicinal Product Dictionary (XEVMPD) and submitted by marketing authorisation holders (MAHs) under the Art.57 (2) legal obligations into the ISO IDMP-compliant data format and terminologies.
In addition to the data stored in XEVMPD, EMA intends to migrate the Centrally Authorised Products (CAPs) data held in its internal database called SIAMED II ultimately building the new ISO IDMP compatible repository
The transformed data will be loaded into the Product Management Service (PMS) hub.
The present chapter provides information on the approach followed by the EMA to enable the transformation and migration of the data to the PMS.
This chapter is purely for information and transparency, it does not require or oblige individual stakeholders to implement this approach in their in-house systems.
New recommendations for injectable veterinary medicines containing procaine benzylpenicillin
The review of the CVMP was limited to the use of these veterinary medicines when administered via intramuscular and subcutaneous routes of administration only.
To ensure an effective use for the proposed indications whilst minimising the risk of antimicrobial resistance development, the Committee concluded that the dose rate and treatment duration for some of the concerned veterinary medicines should be increased. Consequently, for those medicines the meat and offal withdrawal periods in all target species should be increased to ensure consumer safety.
The CVMP considered that the withdrawal periods for milk already provide sufficient assurance of consumer safety and do not need to be amended.
Information on the Member States requirement for the nomination of a pharmacovigilance (PhV) contact person at national level – Human medicines requirements
This document which is based on Pharmacovigilance Inspectors Working group survey, has been updated with new information.
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Draft guideline on ‘Content of the dossier for sterile substances’ released for public consultation
EDQM has drafted a guideline ‘Content of the dossier for sterile substances (PA/PH/CEP (23) 54).
The draft document is now available for public consultation in the consultation space. The consultation deadline for this document is 15 August 2024. After the consultation phase the final guideline will be made available on the EDQM website.
Information related to the consultation phase and the dedicated consultation form are accessible from the consultation space.
HPTLC fingerprinting in two monographs on homoeopathic preparations
The first two monographs, Calendula for homoeopathic preparations (2492) and Chamomilla for homoeopathic preparations (2493), resulting from the pilot study on the use of semi-quantitative high-performance thin-layer chromatography (HPTLC) fingerprinting for homoeopathic preparations containing non-toxic compounds have just been published in Pharmeuropa 36.2 for comment. The method consists in evaluating the intensity of the spot due to the marker in the test solution and comparing it with the intensity of the same spot in a reference solution containing the marker at a known concentration. Marker levels are then evaluated by visual inspection or using appropriate software. The deadline for comments is 30 June 2024
Public consultation on a new general chapter on cell-based preparations for human use in Pharmeuropa 36.2
In response to the need for a text covering the quality of cell-based preparations in the rapidly evolving field of advanced therapy medicinal products (ATMP), the European Pharmacopoeia Commission is proposing a new general chapter, Cell-based preparations for human use (5.32), to its stakeholders.
The chapter provides a framework of requirements for the production and control of cell-based preparations and comprises a definition, an extensive set of general requirements common to all cell-based preparations followed by four detailed individual sections describing additional specific requirements (for human haematopoietic stem/progenitor cells, human chondrocytes, human limbal stem cells and human mesenchymal stromal cells, respectively).
The draft general chapter will remain open for public consultation from April until the end of June 2024.
New European Pharmacopoeia Commission approach to gene therapy
At its 178th session held on 19-20 March 2024, the EPC adopted the general monograph Gene therapy medicinal products for human use (1386) and the accompanying general chapter Additional information on gene therapy medicinal products for human use (5.34), which will replace general chapter 5.14.
In addition to a general requirements section containing provisions on the production of all GTMPs and specific requirements for recombinant vectors and genetically modified cells for human use, general monograph 3186 contains three individual sections describing additional requirements for the classes of GTMPs currently approved in Europe:
genetically modified human autologous cells modified by integrating retroviral or lentiviral vectors;
adeno-associated virus vectors for human use;
oncolytic herpes simplex virus for human use.
The accompanying general chapter 5.34 includes recommendations on product classes that are not yet on the European market to assist users and contains:
the revised remaining sections of chapter 5.14, covering:
plasmid vectors for human use;
adenovirus vectors for human use;
poxvirus vectors for human use;
retroviridae-derived vectors for human use.
a newly drafted section on genetically modified bacterial cells for human use.
In addition, general chapter 5.2.12. Raw material of biological origin for the production of cell-based and gene therapy medicinal products has also been revised to align it with this new approach.
The new general monograph provides a common framework of requirements for GTMPs, while offering the level of built-in flexibility judged necessary for these products, given the rapidly evolving nature of the field.
Ireland
The Health Products Regulatory Authority (HPRA)
Applications for a Variation to a Manufacturer’s Authorisation
This document provides guidance on applying to the HPRA to vary an existing manufacturer’s authorisation. The four appendices available at the end of this document provide detailed guidance on the supporting information required for the inclusion of contract sites based in MRA (mutual recognition agreement) partner territories (Appendix 1), on the import or supply of unlicensed/exempt medicinal products for the Irish market (Appendix 2), guidance regarding Qualified Person declarations (Appendix 3) and remote batch certification by the Qualified Person (Appendix 4).
Combining Multiple Presentations of a Parenteral Product in One Product Authorisation
The guidance in this document applies to Product Authorisations (PAs) issued by the HPRA for parenteral medicinal products for human use, authorised nationally, through mutual-recognition or through the decentralised procedure. The guidance does not apply to medicinal products authorised through the centralised procedure. The guidance is applied by the HPRA as part of new applications and variation applications for parenteral medicinal products.
The purpose of this document is to provide guidance for applicants on the factors that are considered by the HPRA when determining whether it is appropriate to combine different presentations of a parenteral medicinal product in one PA.
Guide to Attainment of Qualified Person Status in Ireland:Educational Requirements, Training and Licensing
The legislation references in this document have been updated.
Guide to Clinical Investigations Carried Out in Ireland
This document has been updated.
United States of America
The US Food and Drug Administration (USFDA)
REMS Logic Model: A framework to link program design with assessment
The REMS logic model is a framework that FDA recommends, which provides applicants with a systematic, structured approach to the design, implementation, and evaluation of a REMS. The aim of applying the REMS logic model is to develop clear goals, objectives, and strategies that align with the intended outcomes and to help applicants incorporate the REMS assessment planning into the design of the REMS.3 The principles in this guidance apply to designing a REMS, developing a REMS assessment, and modifying a REMS.
This guidance is not intended to clarify how risk management or a REMS factors into the benefit-risk assessment of a drug. Although this guidance does not directly address how the Agency determines when a REMS is necessary to ensure that the benefits of the drug outweigh its risks, the concepts discussed in this guidance may be relevant to consider when determining if risk mitigation strategies beyond labeling are necessary.
International
World Health Organisation (WHO)
WHO Technical report Series 1052, 2024
The following new guidance texts were adopted and recommended for use: WHO good manufacturing practices for excipients used in pharmaceutical products (revision); IAEA/WHO good manufacturing practices for in-house cold kits for radiopharmaceutical preparations (new); WHO good practices for pharmaceutical quality control laboratories (revision); WHO/UNFPA female condom generic specification (new); WHO Biowaiver List: proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release (updated), solid oral dosage forms; WHO guideline on Biopharmaceutics Classification System-based biowaivers (revision); and Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (republished). All of the above are included in this report and recommended for implementation.
Products
First vaccine to protect adults from Chikungunya
EMA has recommended granting a marketing authorisation in the European Union (EU) for Ixchiq, the first vaccine in the EU to protect adults 18 years and older against Chikungunya. Chikungunya (also called CHIK fever) is a viral disease caused by Chikungunya virus (CHIKV), a virus transmitted to humans by infected mosquitoes (primarily Aedes aegypti and Aedes albopictus).
There is no licensed treatment for Chikungunya.
CHIKV infections affect people mostly in the tropics and subtropics, and the majority of countries reporting high disease burden are located in Central and South America. The majority of cases in the EU concern travellers who were infected outside of mainland Europe. However, there have been sporadic incidents of onward transmission by infected travellers after their return, mainly in Southern Europe where the Aedes. Albopictus mosquito is established. Spread of the mosquito due to climate change could lead to cases of Chikungunya in regions so far spared.
The CHMP has requested a post authorisation efficacy study to confirm the effectiveness of Ixchiq in preventing Chikungunya in adults.
Conferences
EDQM 4th Training Course on Quality Management for Tissue Establishments (TEs)
A robust quality management system (QMS) is key to ensuring the efficacy, quality and safety of tissues and cells for human application.
This free course will provide TEs in Europe with the tools required to successfully implement a QMS for all their processes, from identification of potential donors to processing and storage of the tissues or cells and final preparation for human application.
European Shortages Monitoring Platform Essentials and Industry Reporting Requirements
The European Shortages Monitoring Platform (ESMP) Essentials and Industry Reporting Requirements Webinar aims to provide an overview of the ESMP and the information that will be reported through it by the pharmaceutical industry once it is operational.
The event is aimed at all Marketing Authorisation Holders (MAHs) in the EU/EEA.
As the first go-live of the ESMP approaches in Q4 2024, launching routine shortage reporting for centrally authorised products (CAPs) by MAHs, this webinar is part of a series of events planned throughout the year to promote awareness and knowledge about the platform.
The webinar will be broadcasted, recorded, and available on the event page shortly after the event.
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.
We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.
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