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Review of Developments in GMP and the Regulation of Medicines August 2022


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INTRODUCTION


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 and Australian regulatory authorities.


The topics covered in this edition of the “Update” include:


UK


Medicines and Healthcare Regulatory Authority (MHRA)

  • Over 285,000 medicines and medical devices seized UK-wide in global action

  • MHRA innovation case studies

  • Horizon Scanning Case Study: Point of Care manufacture

  • Innovation Accelerator

  • Guidance - Export of medical devices

  • Guidance - Project Orbis

  • Annual Report and Accounts 2021 / 2022


EU

EMA

  • ECDC and EMA update recommendations on additional booster doses of mRNA COVID-19 vaccines

  • Further measures to identify and address medicine shortages during public health emergencies adopted

  • OPEN Pilot: One-year review and recommendations

  • Human Medicines Highlights - Issue 160 July 2022

  • First industry standing group (ISG) meeting

  • Big Data Steering Group (BDSG) workplan 2022-25

  • EMA response to the monkeypox public health emergency

  • Concept paper on the revision of the guideline on the chemistry of active substances


EDQM

  • Ph.Eur reference standards

  • General chapter 2.2.46. Chromatographic separation techniques

  • Draft legislative proposal for a new EU Regulation on Blood, Tissues and Cells


USA

  • Identifying Trading Partners Under the Drug Supply Chain Security Act

  • Instructions for Use — Patient Labeling for Human Prescription Drug and Biological Products — Content and Format

  • Changes to Disposable Manufacturing Materials- Q&A


International


Australia

Therapeutic Goods Administration (TGA)

  • Surrogate viruses for use in disinfectant efficacy tests to justify claims against Monkeypox

  • Report on 'Cell, Gene and Tissue Regulatory Framework in Australia: Stakeholder Perspectives' - TGA response

  • TGA approval to change blood donation rules relating to vCJD deferral


International coalition of medicines regulatory authorities (ICMRA)

  • Global regulators agree on key principles on adapting vaccines to tackle virus variants


Products

  • New medicine for multiple myeloma patients with limited treatment options

  • EMA reviewing data on sabizabulin for COVID-19


Documents

  • Documents

  • EFPIA statement on the EU-Turkey WTO Case on Pharmaceuticals



RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Over 285,000 medicines and medical devices seized UK-wide in global action

Officers from the MHRA have seized large quantities of illegally traded medicines and medical devices in an Interpol week of action known as "Operation Pangea".

UK seizures were estimated to be worth around 9 per cent of the global total. 48 social media accounts unlawfully offering to supply medicines were also shut down. Officers from the MHRA Criminal Enforcement Unit searched five premises in the West Midlands and London, with 2 suspects arrested.

During the global week of action coordinated by Interpol, which ran from 23 to 30 June, this year’s ‘Operation Pangea’ saw countries across the world joining forces to seize non-compliant medical products. The operation also involved the arrests of several suspected organised criminals.

MHRA innovation case studies

This is a collection of case studies (including the Horizon Scanning POC study below) demonstrating how MHRA has helped a number of companies navigate the regulatory processes for innovative new medicines and medical devices.

[This makes very interesting reading for the scientist and / or potential patient. MBH]

Horizon Scanning Case Study: Point of Care manufacture

Horizon scanning at the MHRA leads to a proposed new framework to enable the supply and increase in the availability of innovative new medicinal products made at the point of care to patients.

Technology is enabling the creation of new medicinal product types with features such as very short shelf lives, in the range of 30 seconds to a few hours, necessitating manufacturing at the point of care (POC), as well as other highly personalised products. The types of products with these features include Advanced Therapy Medicinal Products (ATMPs), blood products, 3D-printed small molecules and some medical gases.

The current legislative framework is geared for the centralised manufacture of medicinal products which, for each product type, is manufactured in a relatively small number of sites each at large scale. This is primarily because the products have a long shelf life and are then distributed globally to a mass market.

Through horizon scanning and review of the regulatory and scientific advice signals received, MHRA identified a need to amend The Human Medicine Regulations 2012 and The Medicines for Human Use (Clinical Trials) Regulations 2004. These changes are required to create a new framework to enable the supply and increase the availability of innovative new medicinal products made at POC to patients. Legal instructions are being developed to amend these two areas of UK medicines legislation, these changes are made possible by the Medicines and Medical Devices Act 2021. These new Statutory Instruments are due to be laid in Parliament later in 2022. At that time, guidance documents will be developed in consultation with stakeholders.

The UK will be the first country to introduce a tailored framework for the regulation of innovative products manufactured at the point where a patient receives care. MHRA is in discussion with a range of international regulators to support the development of a similar framework in those territories to allow patients to access POC products.

Innovation Accelerator

This guidance provides innovators and developers of innovative products access to MHRA scientific expertise, regulatory guidance and an enhanced advice and signposting service.

Guidance - Export of medical devices

You may need a Certificate of Free Sale (CFS) to export medical devices. To find out, check the import rules of the country to which you are exporting.

The MHRA only issues a CFS as a service to UK exporters for medical devices. A CFS can only be ordered for medical devices and IVDs that have been registered with the MHRA on its Device Online Registration System (DORS). In vitro diagnostic medical devices for performance evaluation cannot be included on CFS orders. A CFS can only be ordered by a UK-based manufacturer, UK Responsible Person or Northern Ireland-based Authorised Representative.

You will have to provide evidence that the medical devices you are exporting have relevant conformity assessment marks (UKCA, CE, CE UKNI)

Guidance - Project Orbis

Project Orbis is a programme to review and approve promising cancer drugs helping patients access treatments faster.

The programme provides a framework for concurrent submission and review of oncology products among international partners. It aims to deliver faster patient access to innovative cancer treatments with potential benefits over existing therapies.

Project Orbis is coordinated by the US Food and Drug Administration (FDA). Alongside MHRA, it involves the regulatory authorities of:

  • Australia (Therapeutic Goods Administration (TGA))

  • Canada (Health Canada)

  • Singapore (Health Sciences Authority (HSA))

  • Switzerland (Swissmedic)

  • Brazil (Agência Nacional de Vigilância Sanitária (ANVISA)

Each country remains fully independent on their final regulatory decision.

MHRA Annual Report and Accounts 2021 / 2022

This report covers the period from 1 April 2021 to 31 March 2022.



Europe


EMA

ECDC and EMA update recommendations on additional booster doses of mRNA COVID-19 vaccines

The European Centre for Disease Prevention and Control (ECDC) and the EMA are recommending that second booster doses of mRNA COVID-19 vaccines be considered for people between 60 and 79 years old and people with medical conditions putting them at high risk of severe disease.

As a new wave is currently underway in Europe, with increasing rates of hospital and intensive care unit (ICU) admissions, it is critical that public health authorities now consider people between 60 and 79 as well as vulnerable persons of any age for a second booster. These could be administered at least four months after the previous one, with a focus on people who have received a previous booster more than 6 months ago. Currently authorised vaccines continue to be highly effective in reducing COVID-19 hospitalisations, severe disease and deaths in the context of emerging SARS-CoV-2 variants.

Further measures to identify and address medicine shortages during public health emergencies adopted

EMA’s Medicines Shortages Steering Group (MSSG) adopted the list of main therapeutic groups of medicines used in emergency care, surgery and intensive care. The list forms the basis from which EMA will draw up concrete lists of critical medicines needed to deal with a specific ‘public health emergency’ or a ‘major event.

The medicines on such concrete lists are closely monitored because of a possible increased risk of shortages. If required, EMA can coordinate swift actions across Member States to ensure continued supply.

EMA recently published the first such list which is focused on COVID-19 medicines.

This is a new responsibility that comes with the reinforced role of the Agency in crisis preparedness and management for medicines and medical devices to monitor shortages and ensure a robust response to major events or public health emergencies.

OPEN Pilot: One-year review and recommendations

With the COVID-19 pandemic, regulatory authorities round the globe faced many challenges including an increased workload coupled with regulatory resources limitations. It rapidly became clear that new innovative approaches and adaptation of regulatory tools and resources were needed to ensure a swift response to COVID-19. With this in mind, the Management Board endorsed the launch of the OPEN Pilot at its 16-17 December 2020 meeting, with the aim of increasing international collaboration in the EU review of COVID-19 vaccines and therapeutics. Collaboration among international regulators was key in the context of COVID-19 and the OPEN pilot facilitated the assessment of the same data by multiple authorities. The pilot enhanced communication channels and facilitated discussions and exchanges. In addition, OPEN allowed regulators to accelerate and align on decisions, leading to fewer labelling differences, while maintaining independence in the decision making. Some opportunities to achieve a greater impact were also identified during the review of the pilot.

The first is that the collaboration could be further enhanced with more detailed rules of engagement and the next steps should focus on improving the operational aspects that facilitate interactions where added value has been identified during the pilot.

A second was the submission gap between applications. Concurrent or near-concurrent application allows for maximum collaboration. This was not a requirement for the pilot, and we saw lower engagement from participating authorities when the submissions were not aligned.

Thirdly, the need for more communication and visibility of the initiative was also identified during the review.

Human Medicines Highlights - Issue 160 July 2022

This newsletter is addressed primarily to organisations representing patients, consumers and healthcare professionals. It provides a summary of key information relating to medicines for human use published during the previous month by the EMA. Information is selected based on recommendations from consulted patients, consumers and healthcare professionals, and does not necessarily cover all relevant information published by the Agency.

First industry standing group (ISG) meeting

EMA has published a report on this first ISG meeting.

The purpose of the ISG is a part of the EMA continuous improvement of industry stakeholders engagement (in line with its industry stakeholders framework), to facilitate regular exchange of views, promote dialogue and receive feedback, a new forum for interactions has been established the industry stakeholders group (ISG).This new forum will be starting, in its pilot phase, with a restricted scope dedicated to industry stakeholders interactions to facilitate timely and efficiently, EMA’s extended mandate implementation and discuss and receive feedback on, for instance, new processes.

Big Data Steering Group (BDSG) workplan 2022-25

The BDSG, set up by EMA and the HMA has published its 3rd workplan that sets key actions to be delivered between 2022–25.

The new workplan will allow to further enhance the efficient integration of data analysis into the evaluation of medicinal products by regulators. Using novel technologies and the evidence generated from big data will benefit public health by accelerating medicine development, improving treatment outcomes and facilitating earlier patient access to new treatments.

The former Big Data Task Force carried out a thorough assessment of the challenges and opportunities posed by big data in medicines regulation, which culminated in 2020 in the publication of data priority recommendations for regulators to generate and use data.

The joint HMA-EMA Big Data Workplan 2022–2025 follows the key recommendations and includes mainly activities related to medicines for human use. However, the scope of some activities covers veterinary aspects, and a separate section in the workplan is fully dedicated to veterinary medicines.

The workplan lays out deliverables and timelines

EMA response to the monkeypox public health emergency

EMA has initiated a series of actions to respond to the ongoing monkeypox outbreak, which has been escalated by WHO to a Public Health Emergency of International Concern (PHEIC). This is the first new PHEIC to be declared since the regulation enforcing EMA’s role in crisis preparedness and management of medicinal and medical devices has become applicable.

Concept paper on the revision of the guideline on the chemistry of active substances

This concept paper addresses the need to review and update the guideline on the chemistry of active substances. This need was recognised in the report on “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines”, which made recommendations to reduce the risk of N-nitrosamines being present in human medicines and to help the European medicines regulatory network be better prepared to manage future cases of unexpected impurities. While in the last few years, experience has predominantly been gained in the management and risk mitigation of N-nitrosamines, it is foreseen that (some of) the principles covered in revised guideline will apply to other ‘cohort of concern’ (CoC) impurities and also other potent toxins released.

The document is released for 3 months of public consultation (until 31/10/22). Following receipt of the comments on the concept paper, the draft for the revised guideline will be prepared and released for 6 months public consultation.


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

Ph.Eur reference standards

Three new Ph. Eur. reference standards and twenty-three replacement batches were released in July 2022

General chapter 2.2.46. Chromatographic separation techniques

This General Chapter has been revised to incorporate the provisions of the pharmacopoeial harmonisation text, signed-off by the Pharmacopoeial Discussion Group (PDG) on 28 September 2021. The revised chapter is now available in the 11th Edition of the Europe Pharmacopoeia (Ph. Eur. 11.0, implementation date: 1 January 2023).

This general chapter applies to chromatographic analytical procedures and supplements the general chapters on Thin-layer chromatography (2.2.7), Gas chromatography (2.2.28), Liquid chromatography (2.2.29) and Size-exclusion chromatography (2.2.30). In addition to definitions of chromatographic features, it contains system suitability requirements for LC and GC procedures, complementing those given in the individual monographs.

For a new EU Regulation on Blood, Tissues and Cells

The European Union (EU) Commission issued its draft legislative proposal for a new EU Regulation on Blood, Tissues and Cells (BTC), in which the EU Commission proposes to leverage on the technical standards and proven expertise of the European Centre for Disease Prevention and Control (ECDC) and the European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe as expert bodies.

This proposal is the result of a comprehensive revision of the existing EU legislation, which has included a wide consultation of BTC stakeholders and international organisations active in the field, such as the Council of Europe/EDQM. Throughout this exercise, the Council of Europe/EDQM has contributed with evidence generated through its activities on substances of human origin (SoHO).

The legislative proposal foresees to leverage on the expertise of the EDQM, which regularly updates widely recognised technical standards under its Intergovernmental Committees.



United States of America


The US Food and Drug Administration (USFDA)

Identifying Trading Partners Under the Drug Supply Chain Security Act

FDA is issuing this guidance to assist industry and State and local governments in understanding how to categorize the entities in the drug supply chain in accordance with the Drug Supply Chain Security Act (DSCSA).

This draft guidance revises the Agency’s previous draft guidance for industry Identifying Trading Partners Under the Drug Supply Chain Security Act (August 2017) to address the status of some entities as trading partners (e.g., private-label distributors, salvagers, and returns processors and reverse logistics providers), provide clarification on certain drug distribution scenarios, and address the interpretation of section 582(a)(7) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which discusses third-party logistics providers (3PL) licensure status prior to the effective date of the forthcoming regulations establishing licensure standards.

Use — Patient Labeling for Human Prescription Drug and Biological Products — Content and Format

This final guidance provides recommendations for developing the content and format of a patient Instructions for Use (IFU) document for human prescription drug and biological products, as well as drug-led or biologic-led combination products submitted under a new drug application (NDA) or a biologics license application (BLA).

The IFU guides the patient on how to safely and effectively use a prescription drug product and commonly includes instructions on preparation, administration, handling, storage, and disposal. The primary purpose of an IFU is to provide detailed, step-by-step written instructions, including visuals if appropriate, in a patient-friendly manner, as visuals can complement written instructions.

Changes to Disposable Manufacturing Materials- Q&A

This final guidance describes chemistry, manufacturing, and controls (CMC) postapproval changes related to disposable manufacturing materials that applicants can pursue in drug and biological product manufacturing.

FDA receives questions about the limited availability of disposable manufacturing materials during periods of increased demand (e.g., public health emergencies or natural disasters).

Limited availability of disposable manufacturing materials can affect sterile drugs and biological products. Applicants should use science-based and risk-based principles, and refer to current guidances for industry, to determine the appropriate reporting category to communicate changes to disposable manufacturing materials. FDA expects all changes to be appropriately managed by an establishment’s pharmaceutical quality system Changes to disposable manufacturing materials for application products should be communicated to FDA through postapproval submissions such as prior approval supplements (PAS) or changes being effected (CBE) supplements, or in annual reports.



International


Australia


Therapeutic Goods Administration (TGA)

Surrogate viruses for use in disinfectant efficacy tests to justify claims against Monkeypox

For sponsors and manufacturers wishing to make label claims of efficacy against Monkeypox for products that are either hard surface disinfectants or disinfectants that are medical devices, the following surrogate viruses can be used in testing to substantiate such a claim:-

  • Vaccinia virus

At this point, no other surrogate viruses have been identified.

Report on 'Cell, Gene and Tissue Regulatory Framework in Australia: Stakeholder Perspectives' - TGA response

In November 2021 the TGA commissioned MTP Connect to conduct a stakeholder review of the regulatory framework for gene, cell and tissue therapies in Australia.

The full report has been published, including MTP Connect's major findings and TGA's proposed response to the major recommendations.

TGA approval to change blood donation rules relating to vCJD deferral

TGA has approved the removal of the geographical deferral of blood and plasma donors from the UK, which was put in place to minimise the risk of variant Creutzfeldt-Jakob disease (vCJD), commonly known as 'mad cow disease'.

This decision follows an application made to the TGA from the Australian Red Cross Lifeblood to remove the deferral which is applicable to blood and plasma donors having spent a cumulative length of time of 6 months or more in the UK between 1980 and 1996.


International coalition of medicines regulatory Authorities (ICMRA)

Global regulators agree on key principles on adapting vaccines to tackle virus variants

Regulators from around the world discussed during a workshop co-chaired by the EMA and the USFDA, emerging evidence to support adaptation of COVID-19 vaccines as the SARS-COV-2 virus continues to evolve. The meeting focused on identifying key principles to support the adaption of COVID-19 vaccines to better match Omicron variants of concern, and on ensuring global regulatory alignment. It was the fourth in a series of workshops on COVID-19 vaccine development and virus variants held by ICMRA.


Products


New medicine for multiple myeloma patients with limited treatment options

EMA has recommended a conditional marketing authorisation in the European Union (EU) for Tecvayli (teclistamab) for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and whose cancer has worsened since receiving the last treatment.

EMA reviewing data on sabizabulin for COVID-19

The EMA Emergency Task Force (ETF) has started a review of data on the use of sabizabulin for treating COVID-19.The review will look at all available data, including data from a study involving hospitalised patients with moderate-to-severe COVID-19 who are at high risk of acute respiratory distress syndrome and death.1 The results of this study indicate that sabizabulin treatment could reduce the number of deaths in these patients compared with placebo (a dummy treatment).Although the developer, Veru, has not yet applied to EMA for an marketing authorisation or a rolling review, the review (based on data from the company) will assist EU Member States who may consider allowing use of the medicine before a possible authorisation.

The review is the first to be triggered under Article 18 of the new EU regulation expanding the role of EMA (Reg 2022/123) during public health emergencies.


Documents


EFPIA statement on the EU-Turkey WTO Case on Pharmaceuticals

The appeal arbitration award by the WTO in the case the EU brought against Turkey on pharmaceutical products, ensures non-discriminatory treatment of EU pharmaceutical exports to Turkey and continued access for Turkish patients to innovative and effective medicines, irrespective of the place of their manufacturing. EFPIA welcomes the swift completion of the appeal arbitration process, and the positive signal this sends for an effective dispute settlement system, one of the core elements underpinning the rules-based global trading system



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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