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Updated: Feb 29

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



EJPPS Vol28.2A
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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:



Medicines and Healthcare Regulatory Authority (MHRA)

  • MHRA to receive £10m from HM Treasury to fast-track patient access to cutting-edge medical products

  • UK members of international criminal gang sentenced to jail for involvement in the illegal sale and supply of prescription medicines

  • Advisory Group Meeting Minute – Reform Proposals

  • Notes for applicants and holders of a Wholesale Dealer’s Licence (WDA(H)) or Broker Registration MHRA Guidance Note 6

  • Patient Involvement Strategy: One year on

  • MHRA trialling pioneering stem cell robot that could transform the availability of life-saving cell therapies

  • MHRA to streamline clinical trial approvals in biggest overhaul of trial regulation in 20 years

  • Extension of CE certificates


  • Advancing regulatory science in the EU – mid-point report published

  • Committee for Advanced Therapies (CAT): Work Plan 2023

  • HMA/EMA multi-stakeholder workshop on shortages

  • Multi-stakeholder workshop on qualification of novel methodologies

  • DARWIN EU® has completed its first studies and is calling for new data partners

  • EMA Management Board: highlights of March 2023 meeting

  • Human Medicines Highlights issue 167

  • Evaluation guide for GMP regulatory compliance programme audit checklist

  • Overview of comments on ICH guideline Q5A (R2) on Viral safety evaluation of biotechnology products derived from cell lines for Human or Animal origin.

  • Big Data highlights

  • European Pharmacopoeia Commission creates new Excipients Strategy (EXS) Working Party

  • CEP 2.0: Use of EMA SPOR/OMS ORG_ID and LOC_ID mandatory for CEP applications.


  • Potency Assay Considerations for Monoclonal Antibodies and Other Therapeutic Proteins Targeting Viral Pathogens

  • Q13 Continuous Manufacturing of Drug Substances and Drug Products

  • Pharmacogenomic Data Submissions

  • Identification of Medicinal Products — Implementation and Use



Australia

Therapeutic Goods Administration(TGA)

  • GMP Clearance: Additional countries added to MRA pathway

  • TGA’s new powers will help reduce the impact of medicine shortages on patients

  • FDA approves first treatment for Friedreich’s ataxia

  • UK MHRA Safety withdrawal of pholcodine-containing cough and cold medicines

  • UK MHRA reclassifies Cialis Together tablets to a Pharmacy medicine


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK

MHRA

MHRA to receive £10m from HM Treasury to fast-track patient access to cutting-edge medical products

A total of £10 million has been awarded to the MHRA to help bring innovative new medicines and medical technologies to UK patients more quickly. The funding will be used to accelerate routes for bringing innovative medical products developed in the UK onto the market, as well as those made and approved by other trusted regulatory partners globally.

The funding over the next two years will support development of a thorough but shortened process to speed up the approval process for cutting-edge treatments developed in the UK with the greatest opportunity to meet the UK’s healthcare priorities, such as cancer vaccines and AI-based therapeutics for mental ill-health.

UK members of international criminal gang sentenced to jail for involvement in the illegal sale and supply of prescription medicines

Three members of an organised criminal gang were sentenced on 13 March 2023 at Stoke Crown Court to jail after pleading guilty to offences relating to the illegal sale of more than three million doses of prescription-only and unlicensed medicines, including controlled drugs, valued at £3.7m. This followed a three-year investigation by the Criminal Enforcement Unit of the MHRA. The defendants now face custodial sentences totalling 68 months.

Advisory Group Reform Proposals

This is an update to the Life Sciences Council Joint Statement on Medical Devices Regulatory Reform.

The Group has taken a patient centred approach, with patient safety and maintaining access to existing and novel products at the core of its discussions. The following detail is a minute of the final Advisory Group discussion.

The ambition continues to be to ensure the UK is the first place to which innovators bring novel HealthTech for approvals and to develop a best-in-class regulatory system that assures and enhances patient safety. The Group agreed the need for these reset proposals to create a step change in the approach to regulation. This builds on the principles in the Taskforce on Innovation, Growth and Regulatory Reform (TIGRR) report to support innovation with proportionate, Outcomes Based Collaborative Regulation. The future work needed should take into account the wider Government work on medicines legislation and the Sir Patrick Vallance Project on the Pro-Innovation Regulation of Technologies.

The Group focussed on three, interrelated areas: international recognition, routes for innovation and system capacity.

Notes for applicants and holders of a Wholesale Dealer’s Licence (WDA(H)) or Broker Registration MHRA Guidance Note 6

As of 8 March 2023, there has been an update to 'Notes for applicants and holders of a Wholesale Dealer’s Licence (WDA(H)) or Broker Registration'-section 9 'Responsible Person'.

Patient Involvement Strategy: One Year On

The MHRA has regulatory responsibilities across the different stages of development of a medicine or device. MHRA calls these stages “the lifecycle”. In this update, it discusses changes it is making to meaningfully engage and involve the public and patients across the regulatory lifecycle. It covers examples of activities between October 2021 to September 2022. It is not intended to detail all progress against the Public Involvement Strategy, rather to highlight the range of activity undertaken during the first year of the strategy.

MHRA trialling pioneering stem cell robot that could transform the availability of life-saving cell therapies

An innovative new robot that grows stem cells, the CellQualiaTM Intelligent Cell Processing System, is being trialled by the MHRA. This robotic system has the potential to bring safer and more cost-effective treatments to people with a wide range of diseases. It is currently the only one in the world outside of Japan, where it was developed.

Stem cells have a unique ability to turn into different types of cells with specialised functions. This makes them particularly useful in medicine because they can replace cells that have been damaged or lost from disease – for example restoring eyesight after corneal disease.

Because stem cell-based therapeutics are difficult to manufacture, their current availability is limited. This means that most treatments for degenerative diseases are focused on limiting the extent of damage rather than fixing the damage that has already occurred. The system being tested at the MHRA has the potential to change this, offering new hope to patients with serious diseases such as Parkinson’s.

This trial is part of a UK-based international research programme, launched in 2021, and a partnership between the MHRA, SAKARTA (a Scottish Regenerative Medicine start-up), and Sinfonia Technology Co. Ltd (a Tokyo-based electrical equipment manufacturer), supported by Foundation for Biomedical Research and Innovation at Kobe (FBRI). The UK Stem Cell Bank is testing the robot over a 12-month period to see whether the cells produced by the fully automated Intelligent Cell Processing System meet the standards needed for them to be used in the manufacture of potentially life-saving treatments.

MHRA to streamline clinical trial approvals in biggest overhaul of trial regulation in 20 years

The legislative changes will help to make the UK one of the best countries in the world to conduct clinical research for patients and researchers. Under the new framework, clinical trials application processes in the UK will be more proportionate, streamlined and flexible without compromising on safety, helping to cement the UK as an attractive destination for trials, including global “multi-site” trials. For example, the integration of the regulatory and ethics reviews of clinical trial applications, which in pilot phase halved the approval times for studies and cut the time from application to recruiting a first patient by 40 days, will be embedded into the new regulation. Comprehensive new guidance will be introduced to accompany the new legislative measures. This will ensure that UK clinical trials truly work in partnership with patients and the public and are representative of the diversity of people who may benefit from the medicine if the data generated ultimately lead to regulatory approval.

Extension of CE certificates

The EU has taken steps to give manufacturers more time to get certain medical devices certified under the EU Medical Devices Regulation (EU MDR). The new arrangements recognise the challenges in capacity across notified bodies.

This is an update to MHRA’s previous announcement in February 2023

MHRA states, “We know that the medical device industry has had concerns about the expiry of certificates. We have been working with them to grant exceptional use authorisations where there is a public health need. We welcome the EU changes to renewals which will mean for many manufacturers supply to the UK can continue without the need for an exceptional use authorisation.”


Europe


European Medicines Agency (EMA)

Advancing regulatory science in the EU – mid-point report published

The mid-term report highlights achievements for the top five human and top three veterinary recommendations thought to deliver the most significant change over the course of the five-year strategy, according to an extensive stakeholder consultation process that took place with EMA’s scientific committees, stakeholders and EU regulatory partners.

In the human domain, progress was made in several areas, including:

  • fostering innovation in clinical trials;

  • promoting use of high-quality, real-world data in decision making;

  • reinforcing patient relevance in evidence generation;

  • contributing to health technology assessment bodies (HTA) preparedness and downstream decision making for innovative medicines;

  • supporting developments in precision medicine, biomarkers and ‘omics.

  • In the veterinary domain, progress was made in several areas, including:

  • transforming the regulatory framework for innovative veterinary medicines;

  • developing new approaches to improve the benefit-risk assessment of veterinary medicinal products;

  • collaborating with stakeholders to modernise veterinary pharmacoepidemiology and pharmacovigilance.

The motivation behind the strategy was the recognition that the pace of innovation had accelerated dramatically in recent years. As part of their mission to promote and protect human and animal health, regulators needed to be ready to support the development and assessment of ever more complex medicines that increasingly deliver healthcare solutions by converging different technologies. Furthermore, the advent of Big Data opened up new sources of information on the use of medicines in healthcare settings. The COVID-19 pandemic also underlined the need for rapid and close engagement of all stakeholders and partners involved in the development and supervision of medicines

Committee for Advanced Therapies (CAT): Work Plan 2023

The activities outlined in the CAT work plan for 2023 have been agreed taking into consideration the Agency’s prioritisation set forth in the EMA multi-annual work programme 2022-2024.

HMA/EMA multi-stakeholder workshop on shortages

The presentations made at this workshop on 01/03/2023 to 02/03/2023 can now be viewed on the EMA website. A video recording will be made available after the event. Processing and publication of the video recording typically takes up to 60 days.

Multi-stakeholder workshop on qualification of novel methodologies

EMA is organising virtual multi-stakeholder workshop on qualification of novel methodologies (17 -18 April 2023). The workshop will bring together academia, learned societies, public-private-partnerships, consortia, patients, HTA bodies, regulators and industry to explore the scope, process and outcomes of the qualification of novel methodologies platform.

The aims of the workshop are to:

  • confirm the future scope of qualification of novel methodologies in the light of ever accelerating development of science and technologies, to best support translation of innovation into patient benefit;

  • look at use case examples of different methodologies, share procedural experiences and solicit input from stakeholders to identify recommendations to future proof the qualification of novel methodologies process and its outcomes.

Interested parties were able to register online until 31 March 2023.

DARWIN EU® has completed its first studies and is calling for new data partners

DARWIN EU®, the Data Analysis and Real-World Interrogation Network, has accomplished its first year of establishment. Following the set-up of the DARWIN EU® Coordination Centre in February 2022, the first ten data partners were onboarded. The network also initiated its first four studies using real-world data (RWD) from across Europe to better understand diseases, populations and the uses and effects of medicines.

DARWIN EU® has ambitious plans for 2023. The network will onboard ten additional data partners and initiate around 16 studies. Data partners can be public or private institutions with access to real-world healthcare data from a variety of sources such as hospitals, primary care, health insurance, registries and biobanks. The call for expressions of interest from potential data partners is now open.

By 2025 DARWIN EU® will be fully operational, delivering around 150 RWE studies per year. The EU’s vision is that by then the use of RWE will have been enabled and value established across the spectrum of regulatory use cases.

EMA Management Board: highlights of March 2023 meeting

The Management Board was updated on the ongoing efforts of EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) to closely monitor several critical shortages of medicines in the EU/EEA, in particular medicines containing the antibiotic amoxicillin.

Since the last Board meeting, the MSSG has been encouraging EU Member States to consider national regulatory flexibilities to allow the distribution of medicines that may not be authorised in their Member States. In addition, EU regulators have met with the main parties involved in the supply chain of amoxicillin to provide regulatory support to increase production capacity.

Other topics covered were:-

  • EMA annual report 2022

  • Veterinary medicines – achievements and challenges

  • Monitoring EMA’s independence policies

  • Experience with mandatory use of CTIS

  • Review of activities of EMA’s working parties

  • Decision of the European Court of Justice (Tecfidera case)


Human Medicines Highlights issue 167

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 European Medicines Agency. 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.

Evaluation guide for GMP regulatory compliance programme audit checklist

Revision 3 of this checklist has been issued and includes API and is common with Canada and PIC/S.

The entire checklist must be used for the assessment/evaluation of GMP regulatory compliance programme as regards active pharmaceutical ingredients and medicinal products. This checklist is used as a high level document. It is meant to detail the “WHAT” and not the “HOW”. The “HOW” is expected to be covered in a lower level document such as a guidance document or a procedure.

Overview of comments on ICH guideline Q5A (R2) on Viral safety evaluation of biotechnology products derived from cell lines for Human or Animal origin.

EMA has now assembled and published this 128 page document.

Big Data highlights

Issue #5 for March 2023 is now available

EDQM

European Pharmacopoeia Commission creates new Excipients Strategy (EXS) Working Party

The EXS Working Party will focus on continuing to address the specificities of these important pharmaceutical ingredients in European Pharmacopoeia (Ph. Eur.) monographs and will also reflect on how best to further develop the Ph. Eur. excipient strategy.

The Ph. Eur. general monograph on Substances for pharmaceutical use (2034) covers both active substances and excipients. However, several parts of this general monograph, as well as the Technical Guide for the Elaboration of Monographs, apply only to active substances. In addition, certain aspects beyond quality – functionality and interactions, for example – are recognised as being specific to excipients. Therefore, in the spirit of continuous improvement, the EPC wishes to assess whether the current approach to these essential and widely used substances is optimal.

The first task will be to take stock of the current situation, reflect on potential areas for development and opportunities for the Ph. Eur. in the future with regard to standard setting for excipients. The aim is to make concrete recommendations to the Ph. Eur. Commission.

Stakeholders will be regularly updated on the outcome of the discussions.

CEP 2.0: Use of EMA SPOR/OMS ORG_ID and LOC_ID mandatory for CEP applications.

It will be mandatory as of 1 June 2023 to provide, in the application forms for new dossiers, sister files and revisions and renewals, the EMA SPOR/OMS ORG_ID and LOC_ID for all companies involved in Certification of suitability (CEP) dossiers. Revised application forms for CEP submissions will be made available shortly.

The ORG_ID and LOC_ID (unique identifiers for an organisation and its locations) will be mentioned on CEPs in addition to companies’ names and addresses. For ongoing submissions, for which a CEP is to be issued, applicants will need to provide the data during the evaluation of the dossier. Companies are therefore encouraged to obtain an ORG_ID and LOC_ID as soon as possible.

ORG_ID and LOC_ID identifiers are assigned and managed by the EMA, using the SPOR/OMS database.


United States of America


The US Food and Drug Administration (USFDA)

Potency Assay Considerations for Monoclonal Antibodies and Other Therapeutic Proteins Targeting Viral Pathogens

The purpose of this guidance is to provide to sponsors recommendations that assist in the development of monoclonal antibodies (mAbs) and other therapeutic proteins that directly target viral proteins or host cell proteins mediating pathogenic mechanisms of infection. A critical quality control measure for these products is the development and implementation of a potency assay(s) adequate to ensure that each lot is produced consistently with the potency necessary to achieve clinical efficacy and that such potency is maintained over the shelf life of the product. This guidance provides detailed recommendations to drug developers with the goal of helping to ensure that drug developers provide adequate information to assess potency at each stage of a product’s life cycle.

Comments should be submitted by 1 May 2023

Q13 Continuous Manufacturing of Drug Substances and Drug Products

This guidance describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). Building on existing International Council for Harmonization (ICH) Quality guidances, this guidance provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products.

Pharmacogenomic Data Submissions

This draft guidance is intended to facilitate progress in the field of pharmacogenomics and the use of pharmacogenomic data in drug development. The draft guidance is intended to clarify the contexts in which pharmacogenomic study findings and data must be included in submissions related to investigational new drug applications (INDs), new drug applications (NDAs), and biologics license applications (BLAs) based on the FDA’s regulations. In addition, this document provides recommendations to sponsors and applicants on the format and content of the pharmacogenomic data submissions.


Identification of Medicinal Products — Implementation and Use

This guidance is for sponsors, applicants, and registrants who are involved in the regulatory submission of medicinal product data. The guidance supports the development and implementation of the International Organization for Standardization (ISO) Identification of Medicinal Products (IDMP) standards for substances, terminologies, and other information for use throughout the global medicinal product development lifecycle. The purpose of these standards is to enable improved accuracy, completeness, and consistency in the international exchange of medicinal product information among stakeholders.


International

Australia

Therapeutic Goods Administration(TGA)

GMP Clearance: Additional countries added to MRA pathway

TGA has assessed the regulatory authorities in the following European countries:-Croatia, Estonia, Romania, Slovenia, and Lithuania.

As members of the European Union (EU), these countries have now been added to the list of those operationalised under the Australia -EU MRA for GMP clearance.

Australian sponsors can now submit GMP clearance applications relying on the evidence produced by these countries’ regulatory authorities. These options were previously not available.

TGA’s new powers will help reduce the impact of medicine shortages on patients

From 22 March 2023, TGA can approve the temporary import or supply of an overseas-approved medicine as a substitute for one that is in short supply if it has been previously registered in Australia. These changes have been introduced to help alleviate the effects of medicine shortages on patients.

This includes medicines that have been discontinued, suspended, or cancelled from the Australian Register of Therapeutic Goods (ARTG) but can still assist patients who don’t have other treatment options.

Previously, TGA could only grant temporary approval for import and supply of a substituted overseas medicine if the Australian medicine was currently included in the ARTG.

These changes will help reduce the impacts that medicine shortages have on Australian patients.


Products

FDA approves first treatment for Friedreich’s ataxia

FDA has approved Skyclarys (omaveloxolone) as the first treatment for Friedreich’s ataxia, a rare, inherited, degenerative disease that damages the nervous system, characterized by impaired coordination and walking.

Patients take Skyclarys capsules orally without food once a day at a recommended dosage of 150 mg.

Friedreich’s ataxia causes progressive damage to the spinal cord, peripheral nerves, and the brain, resulting in uncoordinated muscle movement, poor balance, difficulty walking, changes in speech and swallowing, and a shortened lifespan. Although rare, Friedreich’s ataxia is the most common form of hereditary ataxia in the United States, affecting about one in every 50,000 people.

Safety withdrawal of pholcodine-containing cough and cold medicines

Following a comprehensive scientific safety review of the latest available data on the safety of pholcodine, together with advice from the UK independent Commission on Human Medicines, it has been concluded that the potential risks outweigh the benefits for these products.

There is already a known link between pholcodine and an increased risk of the very rare event of a severe allergic reaction (anaphylaxis) to muscle relaxants (neuromuscular blocking agents) that are used during general anaesthesia in surgery. In September 2022 the findings of a new study further strengthened the evidence of this link, but the overall risk is very small.

The MHRA advises that pholcodine-containing cough and cold medicines are being removed from the UK market as a precautionary measure.

The European Commission has also confirmed its adoption of the EMA Pharmacovigilance Risk Assessment Committee (PRAC) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) final positions on this issue as of 22 March 2023.

Australia’s TGA has decided to cancel the registration of these medicines in Australia and is recalling them from pharmacies.

Of the 55 pholcodine-containing products in Australia, 44 products currently have stock on shelves in Australian pharmacies and are therefore are subject to the TGA's recall.

UK MHRA reclassifies Cialis Together tablets to a Pharmacy medicine

Following advice from the Commission on Human Medicines, the MHRA has reclassified Cialis Together so that it can now be made available for purchase over the counter, without a prescription.


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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