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Updated: Feb 29

Review of Developments in GMP and the Regulation of Medicines September 2023



EJPPS Vol 28.3C Sept 2023
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During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the UK, EU, USA Australian, ICH and WHO regulatory authorities. The topics covered in this edition of the “Update” include: UK MHRA

  • Timeframe for accepting CE marked medical devices in Great Britain extended

  • Labelling and packaging of medicinal products for human use following agreement of the Windsor Framework

  • Regulating medical devices in the UK

  • Implementation of medical devices future regime

  • Supporting patient access to innovation at the heart of new Corporate Plan 2023-26

  • Borderline products: how to tell if your product is a medical device and which risk class applies

  • “Sunset clause” Request for public health exemption from invalidation of a Marketing Authorisation

  • MHRA launches public consultation on reclassification of opioid-containing cough medicine [see Product section]

  • Thousands of unlicensed medical products seized in morning of raids in Bolton

  • MHRA Annual Report and Accounts 2022-2023

  • Class 2 Medicines Recall: B. Braun Medical Ltd, Various Products,

EU


  • EU steps up action to prevent shortages of antibiotics for next winter.

  • Compilation of Union Procedures on Inspections and Exchange of Information

  • Guidance on GMP and GDP: Questions and answers

  • Big Data Workplan 2023-2025

  • Good safety profile of COVID-19 vaccines

  • Medicinal product shortages

  • Q&A on the 'OPEN' Framework

  • OPEN framework extended to a wider range of medicines

  • Phasing out of extraordinary COVID-19 regulatory flexibilities

  • ICH Reflection paper on proposed international harmonisation of real-world evidence terminology and convergence of general principles regarding planning and reporting of studies using real-world data, with a focus on effectiveness of medicines

  • Paving the way towards coordinated clinical trials in public health emergencies in the EU

  • Q&A for marketing authorisation holders/applicants on the CHMP Opinion for the Article5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products - EMA/409815/2020 Rev.16

  • EU steps up action to prevent shortages of antibiotics for next winter

  • Reflection paper on the use of artificial intelligence in the lifecycle of medicines

  • SME Newsletter Issue 59

  • Important update on N-nitrosamine impurities in substances covered by CEPs

  • CEP 2.0: implementation date

  • Outcome of the 176th session of the European Pharmacopoeia Commission

USA

  • Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products.-Draft Guidance

  • CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality

  • CDER collaborates with global regulators on pharmaceutical quality assessments and inspections

International Australia Therapeutic Goods Administration (TGA)


  • Consultation - Review of regulatory requirements for medical devices containing materials of animal, microbial or recombinant origin

  • Public consultation: Proposed application audit framework for medical devices

  • Proposed New Guidelines for the Quality of Listed Probiotic Medicines

International Coalition of Medicines Regulatory Authorities (ICH)

  • ICH Reflection paper on proposed international harmonisation of real-world evidence terminology and convergence of general principles regarding planning and reporting of studies using real-world data, with a focus on effectiveness of medicines


World Health Organisation (WHO)

  • GMP for excipients used in pharmaceutical products (QAS/23.921)

  • Guideline on biopharmaceutics Classification System - based Biowaivers (QAS/23.929 )

Products

  • EMA statement on ongoing review of GLP-1 receptor agonists

  • MHRA launches public consultation on reclassification of opioid-containing cough medicine

  • EMA- First RSV vaccine to protect infants up to 6 months of age and older adults


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS

UK

MHRA

Timeframe for accepting CE marked medical devices in Great Britain extended

The UK Government has made regulations that enable CE marked medical devices to be accepted in Great Britain for defined periods beyond 30 June 2023.This measure aims to support the ongoing and safe supply of medical devices within Great Britain and facilitate a smooth transition towards a future strengthened regulatory framework for medical devices. It is the first statutory instrument in a series that are planned to implement the strengthened framework. Next in the series, the MHRA intends to lay a statutory instrument later this year that will put in place enhanced post-market surveillance requirements.

Core aspects of the future framework for medical devices are intended to apply from 1 July 2025.

Labelling and packaging of medicinal products for human use following agreement of the Windsor Framework

This guidance is designed to provide information on the implementation of labelling and packaging requirements for medicinal products for human use under the Windsor Framework.

The Windsor Framework sets out the long-term arrangements for the supply of medicines into Northern Ireland. It will ensure that medicines can be approved and licensed on a UK-wide basis by the Medicines and Healthcare products Regulatory Agency (MHRA), with medicines using the same packaging and labelling across the UK, and provides for the disapplication of European Union (EU) Falsified Medicines Directive (FMD) requirements for medicines marketed and supplied in Northern Ireland.

To preclude onward movement of these medicines into any part of the European Union (EU), while ensuring medicines use the same packaging and labelling across the UK, all medicines on the UK market must be labelled as ‘UK Only’.

These measures will commence on 1 January 2025

Regulating medical devices in the UK

Updated guidance now that the Government has made regulations that enable CE marked medical devices to continue to be accepted in Great Britain for defined periods beyond 30 June 2023

Implementation of medical devices future regime

MHRA are aiming for core aspects of the future regime for medical devices to apply from 1 July 2025.

Supporting patient access to innovation at the heart of new Corporate Plan 2023-26

A new, visionary Corporate Plan, setting out how the MHRA plans to keep patients safe by enabling access to innovative, safe and effective medical products over the coming three years, has been published.

This plan sets out the central priorities for the agency over the next three years so that it can deliver on this core purpose, by using its breadth of scientific and regulatory expertise, its support for innovation and the risk-proportionate regulation of medical products.

MHRA plans to further embed meaningful patient involvement across the agency’s regulatory pathways and to develop efficacy and safety information that better meets the needs of all patients.

The agency also plans to pilot public awareness activities to increase patient understanding of the Agency’s benefit risk decisions as well as public hearings on major safety issues.

Borderline products: how to tell if your product is a medical device and which risk class applies

This Guidance details how the MHRA makes decisions on when a product is a medical device (borderline products), and which risk class should apply to a medical device.

Some products are hard to distinguish from a medical device, for example products that might be medicines, cosmetics, food supplements, biocidal products or personal protective equipment. These products are called borderline products until their status has been decided.

The MHRA determines whether a product falls within the definition of a medical device and provides information on whether a product is a medical device or not.

For products which are medical devices, MHRA also considers the risk classification applied to the device and whether this is appropriate.

You should not assume that if your product is considered a medical device in countries outside the UK that it will be a medical device in the UK as well. Decisions about whether a product is a medical device are based on the intended purpose of the product and its mode of action (what it is, what it does and how it does it).

[As a consultant, I was once called in to review a company’s early preparation, prior to filing, of a re-purposed facility for the manufacture of a new product. I was surprised to find the company considered its new product to be a Medical Device, rather than a Medicinal Product. It was certainly not clear cut and my advice to the company to seek clarification from MHRA as soon as possible saved the company a lot of money, time to product launch and potential embarrassment, as they would have been using the wrong classification. MBH]

“Sunset clause” Request for public health exemption from invalidation of a Marketing

Authorisation

This update reflects a change to some exemption reasons.

Thousands of unlicensed medical products seized in morning of raids in Bolton

MHRA’s Criminal Enforcement Unit (CEU) seized a quantity of suspected unlicensed medical products following coordinated raids at three residential and six business premises in Bolton, Greater Manchester.

The operation saw raids across nine addresses in Bolton, Westhoughton and Leigh in the early hours of Thursday 13 July 2023, where two women and a man were arrested.

Officers from the MHRA and Greater Manchester Police seized unlicensed medical products including unlicensed versions of Botox, numbing agents and dermal fillers.

MHRA Annual Report and Accounts 2022-2023

This report is now available.

[143 pages in total – but you can be selective in what you read. MBH]

Class 2 Medicines Recall: B. Braun Medical Ltd, Various Products

B. Braun Medical Limited is recalling various product batches as a precautionary measure after traces of midazolam were detected in the batches listed in this notification.

The listed product batches were manufactured following the manufacture of midazolam solution for infusion at the manufacturing facility and therefore some batches were detected to be contaminated with traces of midazolam above the Permitted Daily Exposure (PDE). Based on the analysis, all batches with a confirmed contamination above the safety threshold are included in this notification. Additionally, for solutions that could not be analysed, due to the lack of a reliable method, the batches are also being recalled as a precautionary measure, based on the theoretical risk of midazolam exceeding the safety threshold.

A toxicological assessment has been completed to evaluate the potential risk for patients. The assessment concluded that the highest detected levels of midazolam are deemed to display no clinical effects. Nevertheless, although at low risk, allergic reactions to Midazolam cannot be excluded. B. Braun Medical Limited has not received any reports of suspected adverse drug reactions for the affected batches.

Europe

European Health Union

EU steps up action to prevent shortages of antibiotics for next winter

The European Commission, the Heads of Medicines Agencies (HMA) and the EMA are today issuing recommendations for actions to avoid shortages of key antibiotics used to treat respiratory infections for European patients in the next winter season. These recommendations, which have been developed through the Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG), complement the process to develop an EU list of critical medicines. In close cooperation with the EU Member States, the Commission will take operational follow-up actions, including, if necessary, possible joint procurements.

[Its already a very big global product range (In 2019, the global market for beta-lactam and beta-lactamase inhibitors was valued at around 27.5 billion U.S. dollars, according to market research company NextMSC. By 2030, this market is forecasted to reach a value of 34.2 billion U.S. dollars. - source Statista)

In my experience some companies however see the manufacturing of Beta Lactams as a ‘problem’ that they could do without, partially, because of the need for separate / dedicated facilities and the risk of non-approval of new non Beta Lactam products transferring into a site where Beta Lactams products are still or have previously been made. MBH]

European Medicines Agency (EMA)

Compilation of Union Procedures on Inspections and Exchange of Information

The Compilation of Union Procedures on Inspections and Exchange of Information, formerly known as the Compilation of Community Procedures on Administrative Collaboration and Harmonisation of Inspections, is a tool for facilitating co-operation between the GMP and GDP inspectorates of the Member States and a means of achieving harmonisation. The procedures within it provide the basis for national procedures that form part of the national GMP inspectorates’ quality systems. These quality systems are based on a framework laid down in one of the documents of the Compilation. In July 2010 documents connected with Good Distribution Practice (GDP) inspections started to be added to the Compilation.

The contents of the Compilation are constantly updated, developed and agreed, under the co-ordination of the EMA, by representatives of the GMP Inspectorates of each Member State.

The Compilation has two parts; procedures within the Part I and other documents (e.g. interpretation documents and forms used by regulators) within the Part II. Once agreed by the GMDP Inspectors’ Working Group, documents are reviewed by the European Commission and then published on its behalf by the European Medicines Agency. [297 pages and subject to frequent updating but to my mind -essential reading for many of our members MBH] Guidance on GMP and GDP: Questions and answers The following sections have been updated as of July 2023

  • EU GMP guide part I: Basic requirements for medicinal products: Chapter 7: Outsourced activities

  • Q&A on remote batch certification / confirmation by the qualified person (QP)

  • Q&A on residency of the QP

Big Data Workplan 2023-2025 The vision on Big Data is a strengthened regulatory system that can efficiently integrate data analysis into its assessment processes to improve decision making. Knowing when and how to have confidence in novel technologies and the evidence generated from Big Data will benefit public health by accelerating medicines development, improving treatment outcomes and facilitating earlier patient access to new treatments.

The 4th joint HMA-EMA Big Data Steering Group (BDSG) workplan was adopted in June 2023 and covers activities until 2025.This document introduces each topic and outlines key deliverables.

Good safety profile of COVID-19 vaccines

EMA has endorsed a joint statement on the safety of COVID-19 vaccines issued by the International Coalition of Medicines Regulatory Authorities (ICMRA.

Evidence from more than 13 billion doses of COVID-19 vaccines administered worldwide shows that these vaccines aimed at protecting people from severe outcomes of COVID-19 have a very good safety profile in all age groups, including children and people with underlying medical conditions, immunocompromised patients and pregnant women.

The statement also highlights that vaccines reduce the impact of long COVID based on several real-world data studies and that there is no safety signal from the very large data set held by international regulators suggesting that this condition is a possible side effect of COVID-19 vaccination.

While the vast majority of side effects of COVID-19 vaccines are mild and temporary, safety monitoring systems have identified some very rare (occurring in less than 1 in 10,000 people) but serious side effects. The statement draws attention to the devastating impact of false and misleading information about the safety of COVID-19 vaccines on public health, as it can result in deaths or severe disease if people avoid getting the vaccines they need.

Medicinal product shortages

A new Solidarity Mechanism Working Group advises the Executive Steering Group on setting up a voluntary solidarity forum for EU and European Economic Area (EEA) Member States to seek help from one another in obtaining medicines in case of critical shortages in their own country.

Q&A on the 'OPEN' Framework

International collaboration brings multiple benefits to regulatory authorities, and eventually to patients. It facilitates patient access through harmonisation or convergence, brings additional scientific expertise to the regulatory process, and simplification for the pharmaceutical industry.

EMA began a pilot in December 2020 to increase international collaboration and share scientific expertise on the evaluation of COVID-19 vaccines and therapeutics. Following the positive outcome of the pilot, the framework has been extended to other therapeutic areas.

The following authorities with whom EMA has a permanent confidentiality arrangement in place:

Therapeutic Goods Administration, Australia (TGA), Brazilian Health Regulatory Agency (ANVISA), Health Canada (HC), Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency, Japan (MHLW/PMDA), Swiss Agency for Therapeutic Product (Swiss medic), and the World Health Organization (WHO).

[From the above list it would appear that it is not ‘open’ to either the US FDA nor the UK MHRA ! MBH]

OPEN framework extended to a wider range of medicines

EMA has expanded the scope of the OPEN initiative from COVID-19 vaccines and treatments to a wider range of medicines, such as medicines with the potential to address antimicrobial resistance (AMR), respiratory syncytial virus (RSV) infections or newly diagnosed myelodysplastic syndromes (and other hereditary diseases).

OPEN was established by EMA in December 2020 as a framework to increase international collaboration and share scientific expertise on the evaluation of COVID-19 vaccines and therapeutics, initially as a pilot. It allows regulators from Australia, Brazil, Canada, Japan, Switzerland and the WHO to conduct near-concurrent reviews of certain new medicines and exchange their views and reports on the product assessments. This can help accelerate and align regulatory decisions in several regions in the world, leading to fewer questions for industry and more alignment on the product labelling, while maintaining regulators’ independence in their decision making.

The first product currently being assessed under the new OPEN framework is an mRNA vaccine against RSV, together with Swiss medic. Medicines eligible for assessment under OPEN require EMA’s CHMP and at least one OPEN partner to agree to conduct parallel assessments.

Phasing out of extraordinary COVID-19 regulatory flexibilities

EMA, the European Commission (EC) and the Heads of Medicines Agencies (HMA) are phasing out the extraordinary COVID-19 regulatory flexibilities put in place during the COVID-19 emergency. The extraordinary regulatory flexibilities covered different areas, including marketing authorisation and related regulatory procedures, manufacturing and importation of active pharmaceutical ingredients and finished products, quality variations, labelling and packaging requirements and compliance.

From now on, the regulatory flexibilities that were introduced jointly by the HMA, EC and EMA specifically during the COVID-19 pandemic should no longer be granted. For already approved labelling flexibilities, e.g. the English-only labelling for COVID-19 vaccines, their application will be extended until the end of 2023, in order to ensure a smooth phase-out and avoid any supply difficulties or other disruptions due to a sudden change in applicable requirements.

On-site GMP and GDP inspections, have been restarted after being postponed or carried out remotely during the pandemic, however, a considerable number of postponed inspections still need to be carried out. The validity of GMP and GDP certificates has currently been extended until the end of 2023, and the GMDP Inspectors Working Group will issue in the coming months an update on the approach for 2024. This Group has also reviewed experiences with remote working arrangements of Qualified Persons during the pandemic, and will issue guidance on how those specific arrangements can b applied in the future. EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG). will consider how lessons learned can inform best practices for tackling medicine shortages in case of new and emerging health challenges in the future.

ICH Reflection paper on proposed international harmonisation of real-world evidence terminology and convergence of general principles regarding planning and reporting of studies using real-world data, with a focus on effectiveness of medicines

In July 2022, the International Coalition of Medicines Regulatory Authorities (ICH) expressed its strong support to strengthening international collaboration on activities to enable the use of RWE in regulatory decision-making [ICMRA, 2022]. This statement emphasises the engagement of regulatory agencies across the globe to address current gaps due to the lack of standardisation of RWD/RWE terminology and formats, the heterogeneity of data quality across RWD sources, and the various study designs used depending on the types of diseases, medicines, and regulatory context. Addressing these challenges should be supported by common definitions and best practices. This Reflection Paper outlines a strategic approach for ICH to address some of these challenges. The goal is to further enable the integration of RWE into regulatory submissions and timely regulatory decision-making.

The Reflection Paper was accepted and released for public consultation by EMA’s CHMP on 30 June 2023. The deadline for comment is 30 September 2023.

Paving the way towards coordinated clinical trials in public health emergencies in the EU The actions presented in the report aim to holistically address the barriers and challenges experienced during the COVID-19 pandemic and the outbreak of mpox disease in setting up adequately sized clinical trials across multiple Member States that enable rapid gathering of sufficient, high-quality evidence to support robust decision-making by health authorities across the EU. Proposed actions focus on two areas:-

  • the processing and regulatory approval of large, multinational clinical trials

  • the framework for funding and efficient allocation of resources for clinical trials


The proposed actions will be taken into account by the EC, EMA and the Member States in establishing a concrete roadmap for improved clinical trials during public health emergencies in the EU. Q&A for marketing authorisation holders/applicants on the CHMP Opinion for the Article5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products - EMA/409815/2020 Rev.16 This revision concerns amendment to Q&A 10 to include

  • the Carcinogenic Potency Categorization Approach (CPCA) and the enhanced Ames test (EAT) for establishing AIs for N-nitrosamines.

  • Addition of Appendix 1, listing the nitrosamines for which AI have been established by the Non-clinical Working Party (NcWP), including new AIs for N- nitrosamines determined using the CPCA.

  • Addition of Annex 2, describing the Carcinogenic Potency Categorization Approach for N- nitrosamines.

  • Addition of Annex 3, describing the Enhanced Ames Test Conditions for N-nitrosamines.

Reflection paper on the use of artificial intelligence in the lifecycle of medicines This 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. 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.

The Reflection Paper is part of the joint initiatives to develop the capability in data-driven regulation. It has been developed in liaison between the HMA- EMA Big Data Steering Group (BDSG}, EMA’s CHMP and its CVMP.

The Reflection Paper highlights that a human-centric approach should guide all development and deployment of AI and ML.

The use of AI in the medicinal product lifecycle should always occur in compliance with the existing legal requirements, consider ethics and ensure due respect of fundamental rights.

If an AI/ML system is used in the context of medicines’ development, evaluation, or monitoring, and is expected to impact on the benefit-risk balance of a medicine, EMA advises developers to seek early regulatory support, e.g. through qualification of innovative development methods (for human medicines) or scientific advice.

All interested stakeholders are invited to comment on the draft Reflection Paper and to identify opportunities and risks of AI in the field of medicines. The public consultation is open until 31 December 2023

SME Newsletter Issue 59

This issue is now available

European Directorate for the Quality of Medicines and Healthcare (EDQM)

Important update on N-nitrosamine impurities in substances covered by CEPs On 7 July 2023, the EMA published a revised version of the “Q&A for MA holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products”.

This update includes new scientific approaches for categorisation of N-Nitrosamines and for establishing Acceptable Intakes (AIs), as well as a separate Appendix listing those N-nitrosamines for which AIs have been established by the EMA Non-clinical Working Party (NcWP).

The new approaches and the newly established AIs will also be implemented for CEPs from now on. CEP holders and applicants should:-

  • In those cases where N-nitrosamines have been newly categorised, CEP holders may update their risk assessment, control strategy and their CEP application in accordance with the new AIs and submit a request for minor revision to the EDQM. Similarly, for revisions related to nitrosamine impurities that are currently under assessment, CEP holders are encouraged to proactively update their risk assessment and CEP application in accordance with the newly established AIs and to submit the relevant data to the EDQM.

  • For new N-nitrosamines and those not listed in the Appendix of the EMA Q&As document, the Carcinogenic Potency Categorization Approach (CPCA) described in the EMA Q&As should be used to determine the potency category and associated AI to be considered in the risk assessment and the related control strategy.

CEP 2.0: implementation date

CEP 2.0 will be implemented on 1 September 2023. From that date onwards, new dossier applications and renewal applications will receive a CEP 2.0, whereas revision applications will receive a Hybrid CEP if the content of the CEP has been impacted.

CEP holders will receive their CEP only as a document to be downloaded from the DCEP sharing tool. The validity of CEPs can be checked on the certification database.

Also, as of September, CEP holders having a valid CEP can apply for a switch to CEP 2.0 via a minor revision (to be mentioned in the cover letter) and with a dossier updated according to the CEP 2.0 requirements.

Outcome of the 176th session of the European Pharmacopoeia Commission

The 67 texts adopted at this session by the EPC will be published in European Pharmacopoeia (Ph. Eur.) Supplement 11.5 (January 2024), with an implementation date of 1 July 2024.

These 67 texts included 11 new monographs and three new general chapters. The general chapters are on:-

  • Monocyte-activation test for vaccines containing inherently pyrogenic components (2.6.40),

  • Comparability of alternative analytical procedures (5.27) and

  • Particle size analysis by dynamic light scattering (2.9.50)


The EPC also adopted revised versions of 53 texts.

United States of America

The US Food and Drug Administration (USFDA)

Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products

The management of manufacturing changes presents many challenges for human cellular therapy or gene therapy (CGT) products. Due to the complexity of these products, FDA are providing sponsors of Investigational New Drug Applications (INDs) and applicants of Biologics License Applications (BLAs) for CGT products, with recommendations regarding product comparability and the management of manufacturing changes for investigational and licensed CGT products.

The purpose of this guidance is to provide FDA’s current thinking on management and reporting of manufacturing changes for CGT products based on a lifecycle approach, and comparability studies to assess the effect of manufacturing changes on product quality.

CGT products are regulated under the existing framework for biological products. Manufacturing and control of CGT products can often be affected by unique factors, including limited knowledge of product quality attributes, limited manufacturing experience, limited and variable starting materials, limited amount of product, complex manufacturing processes, and limited product shelf life. These aspects of CGT products may make the management of manufacturing changes more challenging than for other biological products.

A CGT product manufacturer may seek to implement a manufacturing change for a variety of reasons, including improving product quality, expanding product supply, or improving manufacturing efficiency. The risk that a manufacturing change may adversely impact product quality should be prospectively assessed under the manufacturer’s quality risk management processes.

FDA notes that while improvement of product quality is always desirable and encouraged, if the results of comparability studies indicate an improved product quality suggesting a significant benefit in effectiveness and/or safety, the pre- and post-change products may be different products and, therefore, not comparable.

[This latter point would appear to be of significant importance.

Comments on the draft guidance should be submitted to FDA by 12 Sept 2023. MBH]

CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality

This final guidance describes a program at FDA’s Centre for Drug Evaluation and Research (CDER) to make public a comprehensive listing of recognized voluntary consensus standards related to pharmaceutical quality.

FDA’s participation in the development and use of technical voluntary consensus standards has been integral to the execution of FDA’s mission. For example, FDA has used such standards to develop and/or evaluate performance characteristics of dosage forms, testing methodologies, manufacturing practices, product standards, scientific protocols, ingredient specifications, labelling of drug products, and other technical or policy criteria.

This program facilitates submissions by external stakeholders and FDA staff proposing voluntary consensus standards related to pharmaceutical quality for recognition. CDER believes that this program will help promote beneficial innovation in pharmaceutical development and manufacturing and streamline the preparation and assessment of marketing applications for products regulated by CDER.

[Well worth a read MBH]

CDER collaborates with global regulators on pharmaceutical quality assessments and inspections

FDA and the EMA recently completed the first collaborative assessment of a proposed post-approval change for a critical oncology biologic with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) serving as an observer. The work, in which FDA and EMA reviewed and approved a proposal to add new manufacturing and quality control sites, can help assure the supply of the medicine.

This collaboration is the first achievement in an international pilot program conducted as part of the ICMRA Pharmaceutical Quality Knowledge Management System (PQKMS) effort to bring regulators together to enable better industry quality management to reliably supply critical medicines for patients in need.

International

Australia

Therapeutic Goods Administration (TGA)

Consultation - Review of regulatory requirements for medical devices containing materials of animal, microbial or recombinant origin

The TGA periodically reviews requirements for medical devices to ensure they continue to be appropriate. When undertaking such reviews, TGA have regard to the risks and whether those risks have changed over time, international best regulatory practice, and any emerging issues.

The TGA has received requests to review the risk classification of medical devices that contain certain materials from animal, microbial or recombinant origin.

In 2002, when the Medical Device Regulations were established, the risks associated with these ingredients were considered high. Taking into account new and existing feedback from previous consultations, this consultation now seeks to review the regulatory requirements for medical devices containing materials of animal, microbial or recombinant origin to determine whether any changes should be made.

Public consultation: Proposed application audit framework for medical devices

The TGA is responsible for regulating the import, export, and supply of medical devices, including in vitro diagnostic (IVD) medical devices in Australia.

The TGA assesses medical device applications against the regulatory requirements specified in the Therapeutic Goods Act 1989 and the Therapeutic Goods (Medical Devices) Regulations 2002 (the Regulations). Some applications are audited, which is a more thorough assessment.

TGA are seeking feedback on selection of medical device applications for audit and how it conducts these audits.

Proposed New Guidelines for the Quality of Listed Probiotic Medicines

Probiotics are defined as live microorganisms that when administered in adequate amounts, are proposed to confer a health benefit on the host. The quality requirements for listed probiotic medicines are complex to piece together. The purpose of these Guidelines is to help sponsors and manufacturers meet the regulatory requirements to ensure the quality of their probiotic medicine is acceptable under the Therapeutic Goods Act 1989.

International Coalition of Medicines Regulatory Authorities (ICH)

ICH Reflection paper on proposed international harmonisation of real-world evidence terminology and convergence of general principles regarding planning and reporting of studies using real-world data, with a focus on effectiveness of medicines

This Reflection Paper was endorsed by the Assembly in June 2023.

The Reflection Paper presents opportunities for development of new ICH Guidelines and is herewith submitted for public consultation recognising the value of broader input on this topic. Comments received will be considered for inclusion in a finalised Reflection Paper which is anticipated for adoption in June 2024.

Stakeholders are invited to provide comments on this Reflection Paper by 30 September 2023.

World Health Organisation (WHO)

WHO has issued the following two working documents for comment :-

GMP for excipients used in pharmaceutical products (QAS/23.921)

The purpose of this document is to provide guidance for the production, control, storage and distribution of excipients used in pharmaceutical products, focusing on GMP under an appropriate system for managing quality. It is also intended to help ensure that such excipients meet the requirements for quality and purity that they purport or are represented to possess.

Excipients are often used in large quantities in industrial chemistry, as well as the food and cosmetic industry. Specifications for excipients used in these applications may vary and may not always be appropriate for use in pharmaceutical products. It is the responsibility of the finished product manufacturer and of the applicant to ensure that the finished product is manufactured using excipients of a suitable grade conforming to its intended use. Excipients are often used in significant quantities in the production of pharmaceutical products. They should be of appropriate quality as they could affect the quality of finished pharmaceutical products. In general, excipients are used as purchased, with no further refining or purification. Consequently, impurities present in the excipient will be carried over to the finished pharmaceutical product. To achieve the objective of ensuring that excipients used in pharmaceutical products are of appropriate quality, an appropriate level of GMP should be established, implemented and maintained during their production, packaging, repackaging, labelling, quality control, release, storage, distribution and other related activities. Additional measures should be taken when manufacturing excipients for which scientific literature, information in the public domain, or historical data indicate that they present higher risk because of potential formation of toxic impurities during the manufacturing process, or due to potential contamination during storage and distribution. A thorough knowledge and understanding of the processes and associated risks are required. This includes all unit operations and processing steps, key steps in the process, critical parameters (time, temperature, pressure, etc.), environment conditions, equipment used, contamination protection and monitoring points.

Guideline on biopharmaceutics Classification System - based Biowaivers (QAS/23.929 )

The WHO guideline on Biopharmaceutics Classification System - Based Biowaivers will supersede the BCS-based biowaiver section of the WHO guidelines on multisource (generic) pharmaceutical products:- guidelines on registration requirements to establish interchangeability.

The purpose of this document (which is based on the ICH Guideline M9) is to provide recommendations to support the biopharmaceutics classification of Active Pharmaceutical Ingredients (APIs) and the BCS-based biowaiver of bioequivalence studies for Finished Pharmaceutical Products (FPPs).

Products

EMA statement on ongoing review of GLP-1 receptor agonists

EMA’s safety committee, the PRAC, is reviewing data on the risk of suicidal thoughts and thoughts of self-harm with medicines known as GLP-1 receptor agonists, including Ozempic (semaglutide), Saxenda (liraglutide) and Wegovy (semaglutide). These medicines are used for weight loss and for treating type 2 diabetes.

The review was triggered by the Icelandic medicines agency following reports of suicidal thoughts and self-injury in people using liraglutide and semaglutide medicines. Liraglutide and semaglutide medicines are widely used, with an exposure of over 20 million patient- years to date. It is not yet clear whether the reported cases are linked to the medicines themselves or to the patients’ underlying conditions or other factors. Saxenda and Wegovy are authorised for weight management, together with diet and physical activity in people who are obese or overweight in the presence of at least one weight-related health problem. Ozempic is authorised for the treatment of adults with insufficiently controlled type 2 diabetes as an adjunct to diet and exercise but has been used off-label for weight loss.

Suicidal behaviour is not currently listed as a side effect in the EU product information for any GLP-1 receptor agonists.

The review of Ozempic, Saxenda and Wegovy started on 3 July 2023 and has now been extended to include other GLP-1 receptor agonists. This review is expected to conclude in November 2023.

[coincidentally EMA have published a notice regarding shortage of Rybelsus (semaglutide)

3, 7 and 14 mg tablets in certain EU markets. MBH.]

MHRA launches public consultation on reclassification of opioid-containing cough medicine

Health professionals and the public have until 15 August to share their views on the potential reclassification of codeine linctus to a prescription-only medicine.

Codeine linctus is an oral solution or syrup with the active ingredient codeine phosphate and is used to stop a dry cough. The consultation has been launched after considering multiple Yellow Card that codeine linctus is being used recreationally for its opioid effects, rather than for its intended use as a cough suppressant.

First RSV vaccine to protect infants up to 6 months of age and older adults

EMA has recommended granting a marketing authorisation in the European Union (EU) for Abrysvo, a vaccine to protect against disease caused by the respiratory syncytial virus (RSV). Abrysvo is the first RSV vaccine indicated for passive immunisation of infants from birth through 6 months of age following administration of the vaccine to the mother during pregnancy. This vaccine is also indicated for active immunisation of adults aged 60 years and older. The opinion adopted by the CHMP is an intermediary step on Abrysvo’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.

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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