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Updated: Feb 29

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

EJPPS Vol 28.3B August 2023
Download PDF • 284KB


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 PIC/s and Australian regulatory authorities.

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


Medicines and Healthcare products Regulatory Agency (MHRA)

  • Illegal possession and intent to supply prescription medicines

  • Regulating medical devices in the UK

  • Adrenaline Auto-Injectors (AAIs)- [see product section of this Update]

  • Ban lifted on use of UK plasma to manufacture life-saving albumin treatments

  • Guideline on the development and data requirements of potency tests for veterinary cell-based therapy products and the relation to clinical efficacy


  • EMA and ECDC statement on updating COVID-19 vaccines to target new SARS-CoV-2 virus variants

  • Concept paper for the revision of the Guideline on live recombinant vector vaccines for veterinary use

  • Development of a guideline on the quality aspects of mRNA vaccines - Scientific guideline

  • Report - Use of real-world evidence in regulatory decision making

  • ACT EU: creating a better environment for clinical trials through collaboration

  • EMA Management Board meeting

  • Human Medicines Highlights- Issue #170

  • EU Veterinary Big Data Workplan to 2025

  • Revised Policy document on Content of the CEP dossier released for public consultation

  • CEP 2.0: List of authorities and organisations which have access to assessment and/or inspection reports.

  • 2nd edition of Herbal Guide

  • 2022 Highlights – EDQM annual report

  • Ph. Eur. Commission keeps pace with veterinary vaccine development efforts

  • Reference standards


  • Cover Letter Attachments for Controlled Correspondence and ANDA Submissions

  • Nonclinical Evaluation of the Immunotoxin Potential of Pharmaceuticals

  • Formal Dispute Resolution and Administrative Hearings of Final Administrative Orders


The Pharmaceutical Inspection Co-operation Scheme (PIC/S)

  • Bulgaria / BDA and Saudi Arabia / SFDA join PIC/S

  • Changes to the PIC/S Executive Bureau


  • Adrenaline Auto-Injectors (AAIs) - UK

  • Ordines (morphine) oral liquid discontinuation - Australia


  • Up-coming PHSS conferences




Illegal possession and intent to supply prescription medicines worth £2m

A man was sentenced for the illegal possession and intent to supply of prescription-only medication valued at over £2m following investigations by the MHRA.

During 2015, the MHRA was made aware that a website was selling prescription-only medicines illegally.

The MHRA’s Criminal Enforcement Unit investigated the website and, supported by the West Midlands Police, arrested the man at his home in 2016, where he was found to be in possession of over 23,000 sleeping pills, including zopiclone, zolpidem and zolpidem tartrate.

During the arrest, various digital devices and financial documents were seized which showed that bank accounts belonging to the man had received more than £2m from the sale of these medications.

Following the MHRA’s investigation, the Crown Prosecution Service (CPS) brought charges and the man was found guilty following a trial at the Nightingale Court in Wolverhampton.

Regulating medical devices in the UK

Two recent updates have been made to this guidance which covers what you need to do to in order to place a medical device on the Great Britain, Northern Ireland and European Union (EU) markets.

The 16 June 2023 update covers the published overview of timelines for placing CE marked IVDs on the Great Britain market

The earlier revision of 27 April 2023 was primarily to reflect an intended extension to acceptance of CE marked medical devices on the Great Britain market beyond 30 June 2023. This guidance has been updated with changes to ‘Summary of key requirements for placing a device on the Great Britain market’, ‘Registrations in Great Britain’, ‘UKCA marking’, ‘CE marking and Notified Bodies’, ‘Labelling requirements’ and ‘Regulation of medical devices in Northern Ireland’ Reference Guides.

Ban lifted on use of UK plasma to manufacture life-saving albumin treatments

Human albumin (HA) treatments are made of plasma proteins from human blood. They are given to thousands of critically ill patients every year to replace blood loss from trauma such as severe burns or injuries, and those suffering from conditions such as liver disease or sepsis.

However, until recently, the use of UK-donated plasma to manufacture plasma-derived medicinal products has been banned as a safety precaution against the spread of Creutzfeldt Jakob Disease (vCJD). The NHS instead relied exclusively on imported plasma-derived products, primarily from the USA.

In 2020, the ban on using UK-sourced plasma to manufacture immunoglobulins, another type of plasma-derived medicinal product, was lifted.

The MHRA can now confirm that, following further review of the evidence, the CHM has also recommended lifting the ban on treating patients with UK albumin.

[Case studies and other interesting information are included in the Press Release – well worth a read MBH]

Guideline on the development and data requirements of potency tests for veterinary cell-based therapy products and the relation to clinical efficacy

For cell-based veterinary medicinal products it is important to identify and link the biological activity of the viable cells, i.e., their mechanism of action, to the intended clinical indication and ensure batch-to-batch consistency. However, the complex biology of cells and the fact that they may exert multiple biological effects in the recipient can make it difficult to fully uncover and define a mechanism of action and subsequently determine critical potency-related attributes to test. Nevertheless, a potency assay should be able to detect clinically meaningful changes in the quality and/or quantity of the active ingredient in a cell-based veterinary medicinal product and should also serve as stability-indicating parameter.

The aim of this guideline is to provide guidance on the requirements for developing and implementing a suitable potency assay or a combination of assays, which is linked to relevant biological properties of the cell-based product and further to clinical efficacy, while providing the ability to detect changes in the quality and/or quantity of the active ingredient due to manufacturing variability or changes upon stability.


European Medicines Agency (EMA)

EMA and ECDC statement on updating COVID-19 vaccines to target new SARS-CoV-2 virus variants

The European Centre for Disease Prevention and Control (ECDC)and the EMA have issued a Joint statement on adapted COVID-19 vaccines and considerations for their use during the upcoming autumn 2023 vaccination campaigns.

Currently authorised vaccines continue to be effective at preventing hospitalisation, severe disease and death due to COVID-19. However, protection against the virus declines over time as new SARS-CoV-2 variants emerge.

In line with the outcome of recent meetings of international regulators, EMA’s Emergency Task Force recommends updating vaccines to target XBB strains (a subgroup of Omicron), which have become dominant in Europe and other parts of the world.

EMA and ECDC also note that monovalent vaccines (vaccines targeting only one strain such as XBB.1.5) are a reasonable choice to provide protection against current dominant and emerging strains.

Marketing Authorisation Holders in the EU should discuss the revision of the product information for vaccines with EMA’s human medicines committee (CHMP), to reflect the proposed simplified approach.

Concept paper for the revision of the Guideline on live recombinant vector vaccines for veterinary use

The “Guideline on live recombinant vector vaccines for veterinary use” is now over 15 years old, and was developed at a time when only a few vector vaccines were available.

Considering the scientific and regulatory developments since then and experiences gained, the CVMP/IWP considers that this guideline should be updated in order to reflect current knowledge and ensure continued relevance for development of commercial vaccines.

The Immunological Working Party recommends revising the Guideline to consider scientific and regulatory developments since the guideline came into effect and experiences gained. Based on this, it is considered that the following areas in particular will require amendment: definitions, scope, description of the starting materials, safety and efficacy testing. Furthermore, the possibility of using the concept of the vaccine platform technology master file should be addressed

The deadline for comments is September 22 2023.

Development of a guideline on the quality aspects of mRNA vaccines - Scientific guideline

This concept paper addresses the need to establish a guideline on the quality aspects of mRNA vaccines. The number of clinical trial applications for human products and marketing authorisation applications for mRNA containing products significantly increased over the last few years and is expected to increase further in the future. Furthermore, a lot of experience with mRNA vaccines was gained during the COVID-19 pandemic. From an analytical and regulatory perspective, mRNA vaccines are interesting since their classification depends on the target and/or whether they are obtained chemically or biologically.

mRNA vaccines against infectious disease have to align with the general guidance for human vaccines, however the new technology is not fully accounted for in the existing guidance. It is therefore proposed to establish a guideline addressing those specific aspects regarding the manufacturing process, characterisation, specifications and analytical control as well as the definition of active substance and finished product for mRNA vaccines for the prevention of infectious disease.

The concept paper is open for comment until 30 Sept 2023.

Report - Use of real-world evidence in regulatory decision making

Real-world evidence (RWE) from studies led by regulators can complement evidence from other sources including clinical trials. RWE can support both pre-authorisation and post-approval assessments of EMA’s scientific committees, working parties and national competent authorities. However, more effort is needed to better anticipate the need for such studies and to speed up their initiation to ensure that regulators have access to RWE in a timely manner.

The report is part of the Agency’s efforts, alongside the European Medicines Regulatory Network (EMRN), to enable use of RWD in regulatory decision-making.

In pharmacovigilance, it has become mainstay to use routinely collected data about a patient’s health status or the delivery of healthcare from a variety of sources other than traditional clinical trials to support decision-making. However, the use of RWE is less established in earlier stages of medicines development.

The report covers the period from September 2021 until the first anniversary of the Data Analysis and Real-World Interrogation Network (DARWIN EU ®) on 7 February 2023.

During this period, 61 RWD research opportunities were identified, 30 studies initiated and 27 completed. The review considers studies conducted via EMA’s three pathways for RWE generation. Studies performed included safety, drug utilisation and disease epidemiology studies, as well as studies to inform the design and feasibility of clinical trials and clinical management.

The report provides a set of recommendations to address identified opportunities and challenges. These include the need for wider access to additional and complementary data sources, strategies to further accelerate RWE generation as well as earlier identification of research needs, tools to further build capability and capacity for RWE generation and close collaboration with decision-makers and other stakeholders. Further work is needed to fulfil the European Union’s vision to enable the use of RWE and establish its value across regulatory use cases by 2025.

ACT EU: creating a better environment for clinical trials through collaboration

The Accelerating Clinical Trials in the EU (ACT EU) initiative is organising the kick-off workshop for a new multi-stakeholder platform to improve clinical trials in the EU) ACT EU is a collaboration between EMA, the heads of Medicines Agencies (HMA) and the European Commission (EC) that seeks to transform how clinical trials are initiated, designed, and run. The multi-stakeholder platform is a key deliverable of the initiative.

ACT EU aims to place stakeholders at the centre of its activities by giving them the opportunity to steer the direction of the programme. A series of public events bringing together clinical trials stakeholders will be organised during 2023 and 2024 to discuss and agree the model for the establishment of the platform.

EMA Management Board meeting 7-8 June

The European Commission informed the Board about its legal proposals to revise the pharmaceutical legislation, published on 26 April, which aim to make the EU regulatory framework fit for innovative medicines, support greater access to medicines for patients and better address major public health challenges of the future.

The Board acknowledged the crucial role EMA and the European medicines regulatory network played during the pandemic and the transformation the Agency underwent during that period in terms of its regulatory responsibilities.

The Board also noted that EMA remains fully committed to supporting the EU response to the COVID-19 threat and ensuring the timely regulatory review of new or adapted vaccines and therapeutics. Rolling reviews for COVID-19 products will be discontinued, however some COVID-19 related procedures, such as vaccine strain updates, will still be accelerated.

Other achievements highlighted by the Board include EMA’s activities in the global fight against antimicrobial resistance and its contributions to the EU’s Beating Cancer Plan. The chair of EMA's Human Medicines Committee (CHMP) presented recent achievements and ongoing challenges in the area of human health. Among the upcoming challenges and opportunities, the CHMP chair flagged artificial intelligence (AI), real-world data and real-world evidence as crucial tools that will be increasingly used in the regulatory landscape to support the development, authorisation and supervision of medicines in Europe.

Other specific topics covered:-

  • Beating cancer

  • Clinical trials in the EU

  • Network data governance

Human Medicines Highlights- Issue #170 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.

EU Veterinary Big Data Workplan to 2025

The discussions around big data in the veterinary domain have moved from vision to action as the EU Veterinary Big Data workplan to 2025 is endorsed at the Heads of Medicines (HMA) meeting in May 2023.

The EU Veterinary Big Data workplan presented in this document illustrates each topic and key milestones to be carried out until 2025.

The European Directorate for the Quality of Medicines & HealthCare (EDQM)

Revised Policy document on Content of the CEP dossier released for public consultation

EDQM is revising the policy document PA/PH/CEP (04) 1, 6RContent of the dossier for CEP applications for chemical purity and microbiological quality of substances for pharmaceutical use’.

The draft document for public consultation is now available. The consultation deadline is document is 15 September 2023. After the consultation phase the final policy document will be made available on the EDQM website.

CEP 2.0: List of authorities and organisations which have access to assessment and/or inspection reports.

EDQM has published the list of authorities and organisations with which the EDQM has a Memorandum of Understanding and/or Confidentiality Agreement in place allowing them access to assessment and/or inspection reports.

2nd edition of Herbal Guide

This new edition of the Guide for the elaboration of monographs on herbal drugs and herbal drug preparations. It is invaluable for the authors of monographs on these substances, and also helps users of the European Pharmacopoeia (Ph. Eur.) to understand the principles behind the drafting and revision of herbal monographs.

This 2nd edition of the Guide, has been completely overhauled and updated to reflect the latest versions of the relevant monographs and to take account of new Ph. Eur. texts published since the first edition was issued in 2005.

2022 Highlights – EDQM annual report

The EDQM’s 2022 annual report, providing a comprehensive overview of its activities and achievements is now available

The success of the EDQM’s work in European public health systems owes much to both collaboration within the organisation and engagement with external stakeholders. Reinforcing these pillars is an important objective of the EDQM roadmap, the “EDQM 2030” strategic initiative, designed to future-proof operations and activities.

Ph. Eur. Commission keeps pace with veterinary vaccine development efforts

The first DNA vaccine granted a marketing authorisation in the European Union (EU) dates back to 2016 and is intended to protect Atlantic salmon against salmon pancreas disease (SPD) caused by salmon alphavirus subtype 3.

Veterinary vaccine manufacturers have been developing third generation vaccines, including recombinant viral-vector, nucleic acid-based (RNA or DNA) vaccines, for the last three decades. These cover a wide variety of species and diseases. More novel vaccines are currently in the development pipeline and are expected to reach the market in the near future.

To support this emerging field and because the quality, safety and efficacy requirements established for veterinary vaccines should be comparable regardless of their generation, group of experts 15V – the group appointed by the European Pharmacopoeia Commission (EPC) that is responsible for veterinary vaccines – has revised three texts to make it clear that the requirements described in the European Pharmacopoeia (Ph. Eur.) also apply to third-generation vaccines. These three texts, Vaccines for veterinary use (0062), Evaluation of safety of veterinary vaccines and immunosera (5.2.6) and Evaluation of efficacy of veterinary vaccines and immunosera (5.2.7), have been published in Pharm Europa 35.2.

Among the changes made to the three texts, a section on “DNA and RNA vaccines” has been added to the general monograph on Vaccines for veterinary use (0062) and its Definition section has been modified.

Although third-generation vaccines are not covered by the Definition section of individual Ph. Eur. monographs, general chapter 5.2.7 now clearly states that the immunogenicity test described in the individual monographs (when available and applicable) nevertheless applies. It also specifies which individual monograph (live or inactivated) is then to be followed, depending on the situation, e.g. how the immune system is stimulated, the type of insert, if the vector is replication-competent.

Reference standards

Sixteen replacement standards were issued during May.

United States of America

The US Food and Drug Administration (USFDA)

Cover Letter Attachments for Controlled Correspondence and ANDA Submissions

This guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence, original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA. These attachments do not replace the recommendations for the content of cover letters provided in other FDA guidance.

Use of the cover letter attachments contained in the appendices of this guidance is voluntary, and the absence of a cover letter attachment in a submission would not be a basis for a submission to be considered deficient or for a refuse-to-receive (RTR) determination.

Nonclinical Evaluation of the Immunotoxin Potential of Pharmaceuticals

The purpose of this guidance is to assist sponsors in the nonclinical evaluation of the immunotoxin potential of pharmaceuticals. Immunotoxicity is, for the purposes of this guidance, defined as unintended immunosuppression or stimulation (including hypersensitivity), which can include adverse effects of exaggerated pharmacology of pharmaceuticals that are intended to act as immunomodulators.

This guidance applies to drug products, including small molecule drugs and oligonucleotides, as well as certain biological products such as biotechnology-derived therapeutic proteins.

Cell and gene therapies, adjuvanted vaccines, and blood products are not within the scope of this guidance.

Formal Dispute Resolution and Administrative Hearings of Final Administrative Orders

This guidance provides recommendations for industry and review staff on the formal dispute resolution and administrative hearings procedures for resolving scientific and/or medical disputes between the Centre for Drug Evaluation and Research (CDER) and requestors and sponsors of drugs that will be subject to a final administrative order under section 505G of the Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355h).

The drugs that this guidance covers are non-prescription drugs without approved new drug applications, which are governed by the provisions of section 505G (over-the-counter (OTC) monograph drugs). Specifically, this guidance describes the CDER formal dispute resolution (FDR) procedures for eligible requestors or sponsors that wish to appeal a scientific and/or medical issue related to a final order. This guidance also outlines the procedures for an administrative hearing related to a final order. Finally, this guidance describes the procedures for consolidated proceedings for FDR and hearings to resolve scientific and/or medical disputes related to final orders.


The Pharmaceutical Inspection Co-operation Scheme (PIC/S)

Bulgaria / BDA and Saudi Arabia / SFDA join PIC/S

The PIC/S Committee has invited Bulgaria’s Bulgarian Drug Agency (BDA) and Saudi Arabia’s Saudi Food and Drug Authority (SFDA) to join the PIC Scheme.

Bulgaria / BDA will become PIC/S’ 55th Participating Authority and Saudi Arabia / SFDA PIC/S 56th Participating Authority as from# 1 July 2023.

Interestingly, for BDA, the PIC/S assessment was combined with a Canadian MRA assessment and EMA Joint Audit Programme (JAP) audit. A paper assessment was carried out followed by a joint tripartite PIC/S – EMA - Canada MRA on-site assessment visit which took place in February 2023, after establishment of the new system for the GMP Inspectorate of BDA [following a JAP audit in 2018]. The assessment report was finalised in April 2023.

[It is good to see that PIC/s continues to expand its membership which considerably helps spread the standardisation of GMP and also offers the potential for regulators in different countries (where legally possible) to share inspection information and conclusions between members which in turn can reduce the burden of multiple inspections of individual manufacturing sites. MBH]

Changes to the PIC/S Executive Bureau

Following the retirement of the current deputy chairperson, Susan Laska, from her regulatory agency (US FDA), Mr Jacques Morénas (France / ANSM) was elected as new PIC/S Deputy Chairperson - in addition to his current position of PIC/S Sub-Committee on Training (SCT) Chair - and elected Ms Jennifer Burnett (Australia / TGA) as new PIC/S Sub-Committee on Strategic Development (SCSD) Chair.


Adrenaline Auto-Injectors (AAIs)

The UK MHRA has launched new guidance to highlight the latest safety advice on the steps to take during anaphylaxis. This new guidance includes an easy step-by-step guide on what to do in an emergency and provides updated advice on body positioning.

The UK’s Commission on Human Medicines (CHM) Adrenaline Auto-injector Expert Working Group (AAI EWG) was set up to examine a range of issues to support the effective and safe use of AAIs for the emergency treatment of anaphylaxis.

One of the agreed actions for the group was to improve communication channels and develop a communication campaign so that patients, healthcare professionals and the wider public can be better informed and therefore equipped to understand the importance of AAIs as a potential life-saving medicine.

AAIs are intended for self-administration by a patient, or administration by a carer, and should be always carried by patients considered to be at risk of anaphylaxis, so the medicine is available for immediate use, before the arrival of the emergency services. Death from anaphylaxis can occur within a very short period and therefore swift intervention by the administration of AAIs can be lifesaving. AAIs are critical medicines, their effectiveness being of utmost importance.

This update from 19 June 2023 includes a video and an infographic as part of the guidance.

[A somewhat different item to include in these pages, but any of us could have an allergic reaction which could lead to anaphylaxis, or be in a situation where we may need to give assistance. So, I thought it worth including -MBH]

Ordines (morphine) oral liquid discontinuation - Australia

The Therapeutic Goods Administration (TGA) has been notified of Unipharm's intention to discontinue supply of all Ordines (morphine) oral liquid medicines in Australia.

Ordines (morphine) oral liquid is an opioid analgesic medicine used to manage severe pain and difficult or laboured breathing (dyspnoea) in many care settings, including oncology and palliative care. TGA is aware of the importance of these medicines in a range of clinical settings and is treating these discontinuations with high priority. TGA is working with the sponsor of these products, Unipharm, to monitor remaining supplies, as well as a range of other stakeholders, including relevant medical and pharmacy groups, to support treatment continuity for patients.

There are other oral liquid analgesics available in Australia and TGA is closely monitoring the supply of those products for any flow-on impacts.

TGA is also investigating the potential for future approvals for importation and supply of overseas-registered morphine oral liquids under section 19A of the Therapeutic Goods Act 1989


Up-coming PHSS conferences

PHSS Annual Conference in association with UCL Q3P 2023 on 14 09 2023 at Sheraton Skyline Hotel London Heathrow, Heathrow Airport, Bath Rd, Harlington, Hayes UB3 5BP, UK. The conference will address Key challenges in manufacturing and aseptic processing of Biological and Advanced Medicinal Therapeutic products (ATMPs)

PHSS QP Conference on 02/11/2023 at The Glen Yr Afon House Hotel, A472, Usk NP15 1SY, UK. The conference will cover new medicinal products, new technology, new regulations, guidance and standards. Speakers are from the pharmaceutical industry, suppliers to the industry and academia. The conference is geared to practical advice, review of new and current regulatory guidance and involves industry/research/hospital speakers talking through their own processes. Some areas of required CPD are covered

The conference environment is favourable to frank and confidential discussions on Quality Systems and QA/QP responsibilities.

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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