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Updated: Feb 29

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

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EJPPS Vol 28.2C
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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, USA, EU, ICMRA and Australian regulatory authorities.

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

Medicines and Healthcare Regulatory Authority (MHRA)

  • Guidance on registration of certain medical devices which are reusable Class I devices, up-classified Class I devices, and/or reliant on expired/expiring CE certificates

  • New recognition routes to facilitate safe access to new medicines with seven international partners

  • New regulatory pathway set to support safe patient access to innovative medical technologies

  • MHRA and Genomics England to launch pioneering resource to better understand how genetic makeup influences the safety of medicines

  • Patients asked to return Emerade 300 and 500 microgram adrenaline pens for replacement

  • Guidance on QP responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF)

  • Statement on the end of the COVID-19 public health emergency

  • EMA and European medicines regulatory network lift COVID-19 business continuity status

  • Progress with EU-US mutual recognition agreement for inspections for veterinary medicines

  • Guidance for industry to prevent and mitigate medicine shortages

  • EMA annual report 2022 published

  • Pseudoephedrine-containing medicinal products

  • Human medicines Highlights #169

  • Ph. Eur. Commission kicks off elaboration of three general texts on mRNA vaccines and components

  • Reference standards

  • PDG makes significant progress in its harmonisation efforts

  • Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High Risk Drug Components for Diethylene Glycol and Ethylene Glycol

  • Q9(R1) Quality Risk Management

  • Global regulators agree on way forward to adapt COVID-19 vaccines to emerging variants


Therapeutic Goods Administration (TGA)

  • Final decision to reduce paracetamol pack sizes.

  • Update to listed medicine ingredients

  • TGA supports MHRA’s new international recognition framework for medicines


  • Report from the HMA/EMA multistakeholder workshop on medcines shortages in the EU




Guidance on registration of certain medical devices which are reusable Class I devices, upclassified Class I devices, and/or reliant on expired/expiring CE certificates

This revision to the guidance covers changes to the MHRA Device Registration System (DORS) instructions for Scenarios 1 to 4 in the Guidance on registration of medical devices with an expired or expiring CE Certificate.

New recognition routes to facilitate safe access to new medicines with seven international partners

New regulatory recognition routes for medicines will be established using approvals from Australia, Canada, the European Union, Japan, Switzerland, Singapore and the United States. The new international recognition routes will sit alongside the MHRA’s own unique innovation pathway for medicines which integrates early regulatory advice with health technology assessment advice.

The new framework will allow the MHRA to make the most of the expertise and decision-making of trusted regulatory partners to streamline assessments of specific products. As a result, cutting-edge medicines that have been approved in other countries will get to UK patients more quickly, with cost reductions and streamlined regulatory processes for industry. As a sovereign regulator, the UK regulator will still be responsible for approving all ‘recognition route’ applications under the new framework, At the time of the UK’s exit from the European Union, the MHRA introduced temporary routes to market for European approved products in Great Britain, known as EU ‘reliance’ routes, to ensure that patients could continue to have timely access to new treatments. These temporary routes are due to expire at the end of 2023.

New regulatory pathway set to support safe patient access to innovative medical technologies

Plans are advancing for a new regulatory pathway that facilitates the development of innovative technologies, by providing innovators and manufacturers with a multi-partner support service including targeted scientific advice that brings new products to patients sooner.

The Innovative Devices Access Pathway (IDAP), set for launch later in 2023, will be operated by the MHRA, the National Institute for Health and Care Excellence (NICE), Health Technology Wales (HTW) and Scottish Health Technology Group (SHTG).

Innovators of medical technology (commercial or non-commercial, UK based or international) that addresses clinical needs are being encouraged to register for further information ahead of a planned 2023 pilot launch. Once up-and-running, the IDAP partners will use the lessons learned from the pilot to help develop the future IDAP pathway, creating an end-to-end visible framework that supports innovators generate the evidence they need to achieve regulatory approval, heath technology assessment decisions, and patient access in the NHS.

MHRA and Genomics England to launch pioneering resource to better understand how genetic makeup influences the safety of medicines

MHRA will be the first drug safety regulator in the world to pilot its own genetic ‘biobank’, launching 1 June 2023

A brand-new genetic research resource, known as a ‘biobank’, will be piloted by the MHRA in a joint venture with Genomics England to better understand how a patient’s genetic makeup can impact the safety of their medicines.

The Yellow Card biobank, which will contain genetic data and patient samples, will operate alongside the MHRA’s Yellow Card reporting site for suspected side effects and adverse incidents involving medicines and medical devices. It forms part of a long-term vision for more personalised medicine approaches, as scientists will use the repository of genetic information in the biobank to determine whether a side effect from a medicine was caused by a specific genetic trait. This will in turn enable doctors to target prescriptions using rapid screening tests, so patients across the UK will receive the safest medication for them, based on their genetic makeup.

Patients asked to return Emerade 300 and 500 microgram adrenaline pens for replacement

Patients, or carers of patients, who carry Emerade 300 or 500 microgram adrenaline auto-injector pens should immediately contact their GP to obtain a prescription for, and be supplied with two 300 microgram or 500 microgram auto-injectors of a different brand. Patients should only return their Emerade pens when they have received a replacement from their pharmacy which will be an alternative brand - either EpiPen or Jext.

This precautionary recall is because some 300 microgram and 500 microgram Emerade auto-injector pens may rarely fail to activate if they are dropped, meaning a dose of adrenaline would not be delivered. Premature activation has also been detected in some of the 300 microgram and 500 microgram pens after they have been dropped, meaning that a dose of adrenaline is delivered too early.

The activation failure and premature activation was detected during a design assessment conducted by the manufacturer.

Guidance on QP responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF)

New guidance has replaced the previous section; 'Notification of QPPV and PSMF details to the MHRA by existing holders of UK marketing authorisations'. This guidance replaces the previous requirement to submit a Type IA(IN) variation and an accompanying eCTD sequence to make these changes. This has been simplified and only an update notification is required, there is no requirement to submit an eCTD sequence.


European Medicines Agency (EMA)

Statement on the end of the COVID-19 public health emergency

The EU Vaccine Strategy made sure that each and every EU country was able to have access to safe, effective and high-quality vaccines and therapeutics to protect their citizens. EMA provided robust scientific recommendations, timely evaluation of new vaccines and therapeutics - adapting its recommendations as the virus evolved - and helped mitigate shortages.

Throughout the pandemic, waves of disinformation undermined trust in EMA’s work and scientific expertise and, ultimately put millions of lives at risk. We shouldn’t forget that it was science that brought us the vaccine breakthroughs, it was science that freed us from the lockdowns, and it was scientists who provided the trusted, factual information when it mattered most.

Overall, EMA initiated new and agile ways of working, many of which are here to stay. EMA’s response was built on unprecedented collaboration and a united sense of purpose across regulators, developers, institutions and citizens. It was supported by the tireless commitment and work of countless experts from the regulatory authorities – at EMA and at national level.

COVID-19 remains a global health threat, and with the risk of emergence of new variants, we cannot let our guard down. EMA remains fully committed to supporting the EU response to the COVID-19 threat and ensuring that new or adapted vaccines and therapeutics can be made available as needed.

As the pandemic unfolded and public health responses quickly adapted to the emerging threat, it was clear that our societies weren’t ready for a crisis of this scale. As we look ahead, and prepare for new and emerging health challenges, we should not forget the sheer scale of this health emergency. We are working to make sure that the lessons learned during the COVID-19 pandemic are used to prepare better for any future public health emergency that we might face.

In terms of our operations, EMA will now make adjustments regarding certain activities that are only needed or are even reserved for these types of crises. EMA will provide updates about these changes in the coming weeks.

EMA and European medicines regulatory network lift COVID-19 business continuity status

EMA and the European medicines regulatory network are lifting their respective COVID-19 business continuity measures after successfully handling the unprecedented operational challenges posed by the pandemic.

EMA's business continuity plan was introduced in 2020 to ring-fence resources to deal with COVID-19 while safeguarding the continuity of the Agency's core activities related to the evaluation and supervision of medicines during the pandemic.

While the temporary measures that were introduced to cope with the peak impact of the COVID-19 pandemic are no longer required, resourcing within the entire European medicines regulatory network remains a challenge. EMA will continue to work closely with the Heads of Medicines Agencies (HMA) from the Member States to identify and implement sustainable solutions. Experiences gathered during application of the EMA and network business continuity plans, as well as lessons learnt during the pandemic, will inform this work.

Progress with EU-US mutual recognition agreement for inspections for veterinary medicines

The EU and the USA have made important progress towards enabling mutual recognition of inspections of manufacturing facilities of certain veterinary products. The US FDA has recognised the capability of 16 EU Member States to carry out GMP inspections for certain veterinary products at a level equivalent to the USA. At the same time, the EU also recognised the FDA as an equivalent authority for GMP inspections of sites manufacturing veterinary medicines.

This follows the extension of the scope of the MRA between the EU and the US to veterinary products on 11 May 2023.

The Member States whose GMP inspections for veterinary medicines are recognised by the FDA are Austria, Belgium, Bulgaria, Denmark, Estonia, Finland, France, Greece, Hungary, Ireland, Luxembourg, Netherlands, Poland, Portugal, Slovenia and Spain.

Teams from the European Commission (EC), EU National Competent Authorities(NCAs), EMA and the FDA continue working closely to ensure the timely assessment of the remaining 11 competent authorities of Member States now that the difficulties brought about by the COVID-19 pandemic have been largely removed.

From now on, the FDA should rely on inspections conducted by these 16 Member States also for veterinary products and EU Member States and EMA will rely on inspections conducted by the FDA.

Readers should note in the updated Q&A, question 11 relating to import testing of veterinary products into the EU from USA.

Guidance for industry to prevent and mitigate medicine shortages

Medicine shortages are a global health problem and are increasingly affecting European countries. Shortages can lead to medicine rationing and delay in critical treatments, with a significant impact on patient care. In addition, patients may need to use less effective alternatives and face an increased risk of medication errors. Ensuring the availability of authorised medicines in the European Union (EU) is a key priority for EMA and the European medicines regulatory network.

The guidance describes the various stakeholders involved in the medicine supply chain and their responsibilities and role in the prevention and management of medicine shortages. It provides ten recommendations for marketing authorisation holders, wholesalers, distributors and manufacturers to minimise the occurrence of medicine shortages and their impact.

Key recommendations include:-

  • informing national competent authorities of potential or actual shortages as early as possible and providing detailed information to better predict the possible impact and implement preventive measures;

  • establishing robust shortage prevention and shortage management plans;

  • optimising pharmaceutical quality systems and increasing resilience of complex, multinational supply chains;

  • timely communication between the various stakeholders in the medicine supply chain;

  • general principles to promote fair and equitable distribution of medicines to meet the needs of patients.

EMA annual report 2022 published

The report provides an overview of the Agency’s activities to protect and promote public and animal health in the European Union (EU).

The digital report outlines the most important highlights regarding the evaluation and monitoring of human and veterinary medicines and a selection of key figures. It also contains an interactive timeline of important milestones in 2022, with advanced functionalities that allow readers to explore each topic in more depth by accessing additional documents, audio-visual materials and infographics.

The report includes an overview of EMA’s recommendations on vaccines and treatments for COVID-19 and for mpox. In addition, it highlights the Agency’s activities carried out to implement the EU regulation reinforcing EMA’s role in crisis preparedness and management for medicinal products and medical devices. The report also showcases how EMA continued to address public and animal health needs beyond the ongoing public health emergencies.

In 2022, EMA recommended the authorisation of 89 medicines for human use, including 41 with a new active substance. Many represented significant progress in their therapeutic areas.

Pseudoephedrine-containing medicinal products

EMA’s safety committee (PRAC) has started a review of medicines containing pseudoephedrine following concerns about the risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), conditions affecting blood vessels in the brain. Pseudoephedrine is taken by mouth and is used alone or in combination with other medicines to treat nasal congestion (a blocked nose) resulting from a cold, flu or allergy.

The review follows new data from a small number of cases of PRES and RCVS in people using pseudoephedrine-containing medicines which were reported in pharmacovigilance databases and the medical literature.

Pseudoephedrine-containing medicines have a known risk of cardiovascular and cerebrovascular ischaemic events (side effects involving ischaemia in the heart and brain), including stroke and heart attack. Restrictions and warnings are already included in the medicines’ product information to reduce these risks.

Considering the seriousness of PRES and RCVS, the overall safety profile of pseudoephedrine and the indications for which the medicines are approved, the PRAC will review available evidence and decide whether the marketing authorisations for pseudoephedrine-containing medicines should be maintained, varied, suspended or withdrawn across the EU.

Human medicines Highlights #169

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


Ph. Eur. Commission kicks off elaboration of three general texts on mRNA vaccines and components

Messenger RNA (mRNA) vaccines have been at the forefront of vaccine development efforts during the COVID-19 pandemic. With two authorised mRNA-based vaccines on the market, the mRNA vaccine field continues to evolve, as this increasingly important technology can be tailored to fight different infectious diseases. More products currently in development are expected to reach the market in a relatively short time and multivalent vaccines may also soon follow.

To support this emerging field, the European Pharmacopoeia Commission (EPC) agreed, at its 175th session in March 2023, to elaborate three new general texts addressing aspects related to the production and control of mRNA vaccines and their components, namely:

  • mRNA Vaccines for human use (5.36), the mRNA packaged in lipid nanoparticles, i.e. mRNA-LNP medicinal product;

  • mRNA Substances for the production of mRNA vaccines for human use (5.39), the mRNA active substances in the manufacture of mRNA vaccines;

  • DNA Template for the preparation of mRNA transcript (5.40), the starting material for the preparation of the mRNA component.

Addressing the quality of mRNA vaccines and their components has been identified as a significant ongoing project for the EPC in the field of nanomedicines, and preparing for a more comprehensive incorporation of these medicines in the European Pharmacopoeia (Ph. Eur.) is among its priorities for 2023-2025.

[New technology, new vaccines and new guidance to facilitate them getting safely to the market. Above all new hope of new cures /prevention of infection for patients. Truly a new horizon MBH]

Reference standards

One new Ph. Eur. reference standard and eighteen replacement batches released in April.

16 replacement batches released in May 2023

PDG makes significant progress in its harmonisation efforts

The Pharmacopoeial Discussion Group (PDG) works to harmonise the technical content of selected excipient monographs and general chapters. An important step forward in the harmonisation effort has been achieved recently for a number of texts.

Numerous texts have been signed off since the PDG October 2022 meeting and are now available on the Pharmacopoeial Harmonisation section of the EDQM website. These include:

  • a new text on Particle Size Analysis by Dynamic Light Scattering (G-21),

  • a revision of the general chapters Bulk Density of Powders (G-02) and Powder Flow (G-05),

  • a number of corrected texts and modified excipient monograph sign-off cover sheets.

The corresponding revised Ph. Eur. texts are scheduled to be published in Supplements 11.4 and 11.5.

Two revised and harmonised texts, general chapter 2.9.1. Disintegration of tablets and capsules and the monograph on Maize starch (0344), have been published for public consultation. The revised texts remain open for public consultation until 30 June 2023. Both texts will also soon be published for public consultation by the JP and USP in their respective fora. Comments will be discussed by the relevant groups of experts and within the PDG before aligning the revised sign-off texts.


Global regulators agree on way forward to adapt COVID-19 vaccines to emerging variants

International regulators EMA FDA, ICMRA have published a report highlighting the outcomes of their discussions on COVID-19 vaccines and the need for and strategy to update their composition based on the emerging evidence on coronavirus SARS-CoV-2 variants and lessons learned from previous vaccine updates. Currently authorised vaccines continue to be effective at preventing hospitalisation, severe disease and death due to COVID-19. However, protection against infection wanes over time and as new SARS-CoV-2 variants emerge. Preliminary data show that COVID-19 vaccines adapted to the currently circulating strains improve immunity to recently emerged variants, such as XBB descendent lineages. They noted that only data on manufacturing and quality of the vaccine and laboratory data would be required for the authorisation or approval of strain changes for the already authorised COVID-19 vaccines, provided that post-authorisation data regarding vaccine quality, effectiveness, immunogenicity and safety data are collected.


Therapeutic Goods Administration(TGA)

Final decision to reduce paracetamol pack sizes

TGA has published a final to reduce the maximum size of packs for various paracetamol products.

Each year in Australia around 225 people are hospitalised and 50 Australians die from paracetamol overdose, with rates of intentional overdose highest among adolescents and young adults. This decision aims to reduce the harm from intentional overdose.

From 1 February 2025, new restrictions on paracetamol will:

  • reduce the maximum size of packs available for general sale (e.g. supermarkets and convenience stores) from 20 to 16 tablets or capsules

  • reduce the maximum size of packs available in pharmacies without the supervision of a pharmacist (i.e. ‘Pharmacy Only’ packs) from 100 to 50 tablets or capsules.

  • make other pack sizes of up to 100 tablets or capsules available only under the supervision of a pharmacist (‘Pharmacist Only’ medicines).

Paracetamol tablets and capsules for both general and Pharmacy Only sale will also be required to be in blister packaging. The maximum size of Pharmacy Only packs of individually wrapped powders or sachets of granules containing paracetamol will also be reduced in line with tablet and capsule packs.

To further minimise the harm from paracetamol overdose, the TGA is encouraging retailers such as supermarkets to restrict sales to a single pack at a time.

To allow manufacturers and retail outlets sufficient time to adjust, the decision takes effect from 1 February 20

Update to listed medicine ingredients

39 listed medicine ingredients and requirements for their use have been updated in the Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2023, which commenced on 1 May 2023.

TGA supports MHRA’s new international recognition framework for medicines

As a trusted regulatory partner, TGA is committed to support the new international recognition framework that the UK MHRA is introducing for medicines.

TGA works closely with other regulators and relies upon its international networks in the regulation of prescription medicines, where possible to reduce the regulatory burden on sponsors and bring safe and effective products to patients as quickly as possible.


Report from the HMA/EMA multi-stakeholder workshop on medcines shortages in the EU

In 2016, HMA/EMA Task Force on Availability of Authorised Medicines for Human and Veterinary Use (TF AAM) was set up to look for strategic and structural solutions to address disruptions in the supply of medicines and ensure their continued availability in the EU. The work of the taskforce led to a number of initiatives, including EU-wide guidance to improve the management of medicine shortages in the EU and the EU Single Points of Contact for Shortages (SPOC) network.

The COVID-19 pandemic compounded the problem of medicine shortages and EMA initiated several activities to better monitor and coordinate actions on shortages in crisis situations within the EU regulatory network. The new structures and activities, which were set up without a formal mandate during the COVID-19 pandemic, were then enshrined in legislation last year (EMA’s extended mandate) to ensure better management of shortages during times of crisis.

On 1 and 2 March 2023, acknowledging the important role stakeholders play in the prevention and management of shortages, the Agency convened a workshop bringing together national competent authorities (NCAs), the European Commission (EC), industry, patient and healthcare professional representatives, health technology assessment bodies, payers and academia as well as veterinary medicine representatives. During the workshop, these stakeholders discussed recent initiatives and reflected on possible actions to better and more proactively prevent, mitigate and manage medicine shortages in Europe.

The workshop provided an opportunity for stakeholders to reflect on the work of the TF AAM and to identify next steps needed to become more proactive and focus on preventative actions to better anticipate and manage emerging situations.

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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