Review of Developments in GMP and the Regulation of Medicines February 2024
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 WHO regulatory authorities.
The topics covered in this edition of the “Update” include:
UK
Regulatory Roadmap to support safe access to medical technology including AI and Diagnostics
MHRA introduces new restrictions for fluoroquinolone antibiotics
New safety information for omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000 mg capsules)
MHRA update on new study on risk in children born to men taking valproate
Illegal medicines worth more than £30 million seized in the UK in 2023
List of medicines that cannot be exported from the UK or hoarded
Two new UK Approved Bodies, delivering increased capacity for the certification of the performance and safety of medical devices
EU
Major update of the SME user guide
Veterinary medicines: Highlights of 2023
EMA confirms measures to minimise the risk of serious side effects with medicines containing pseudoephedrine
EMA to support establishment of the African Medicines Agency
New platform for collection of sales and use data of antimicrobials in animals
Clinical trials' transition to new EU system - one year left
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Pharmeuropa 36.1
The template of Quality Overall Summary (QOS) to be submitted for Certification applications has been adapted to the current needs!
CEP holders invited to comment on draft monographs published in Pharmeuropa 36.1
At its 177th session in November 2023, the European Pharmacopoeia Commission (EPC) approved the strategy for N-nitrosamine impurities in individual monographs.
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies
USA
Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin
Revising ANDA Labeling Following Revision of the RLD Labeling Guidance for Industry
Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products
International
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
PIC/S-EMA-WHO Joint Implementation Working Group
6th PIC/S Expert Circle Meeting on Good Distribution Practice (GDP)
World Health Organisation (WHO)
WHO decision improves children’s access to safer polio vaccine Australia
Australia
Therapeutic Goods Administration (TGA)
Repeal of Therapeutic Goods (Restricted and Prohibited Representations—Nicotine)
Nitrosamine impurities acceptable intakes update Products
Products
Rezzayo approved in UK to treat adult patients with invasive candidiasis
Conferences
PHSS sterile product manufacturings and aseptic processing conference
MHRA Good Pharmacovigilance Practice (GPvP) Symposium
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
Medicines and Healthcare products Regulatory Agency (MHRA)
Regulatory Roadmap to support safe access to medical technology including AI and Diagnostics
This new roadmap for new regulations, from the MHRA, will enhance the UK’s ability to benefit from rapidly advancing medical technology, offering significant new opportunities for patients and healthcare.
Transformative technologies such as new implantable devices, healthcare AI and software, and diagnostics for early detection and prevention of disease, all demand a new regulatory framework.
The MHRA’s roadmap sets out a route to deliver enabling regulation via a series of new Statutory Instruments (SIs).
Priority measures to protect patient safety will be put in place this year, with core elements of the new framework intended to be in place by 2025.
The planned regulations are also designed to deliver greater international harmonisation, with more patient-centred, proportionate requirements for medical devices which are responsive to technological advances.
MHRA introduces new restrictions for fluoroquinolone antibiotics
Fluoroquinolone antibiotics given systemically (by mouth, injection, or inhalation) must only be administered when no other antibiotics are appropriate for use. This means that fluoroquinolones should only be prescribed when other recommended antibiotics have failed, will not work due to resistance, or are unsafe to use in an individual patient.
This is a strengthening of the previous regulations which stated that fluoroquinolones should not be prescribed for mild to moderate or self-limiting infections, or non-bacterial conditions.
The restrictions have been introduced following Yellow Card reports from patients who have experienced long-lasting or disabling reactions following use of fluoroquinolones, in some cases prescribed for mild to moderate or self-limiting infections, or non-bacterial conditions.
New safety information for omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000 mg capsules)
MHRA has added atrial fibrillation (abnormally fast and irregular heartbeat) to the safety information of medicines containing omega-3-acid ethyl esters that are licensed for the treatment of hypertriglyceridaemia when changes to the diet alone have not worked. Hypertriglyceridaemia is a medical condition in which there is too much of a certain type of fat called triglycerides in the blood, which can increase the risk of coronary heart disease and cause inflammation of the pancreas (pancreatitis).
These medicines are available on prescription or as pharmacy medicines (behind the counter) in the UK and should not be confused with omega-3 dietary supplements. Anyone taking these medicines for hypertriglyceridemia must seek medical attention if they develop symptoms of atrial fibrillation, such as palpitations, dizziness, shortness of breath and tiredness. Patients should not stop their hypertriglyceridaemia treatment without speaking with their doctor but should inform their healthcare professional of any current or past heart problems before using these medicines.
Healthcare professionals are advised to stop and discontinue treatment with these medicines should a patient develop atrial fibrillation.
MHRA update on new study on risk in children born to men taking valproate
As part of its ongoing monitoring of the safety of valproate, MHRA continues to rigorously review all emerging data. This includes a new study on outcomes in children whose fathers took valproate at the time of conception commissioned by the European Medicines Agency,
This study suggests there may be an increased risk of neurodevelopmental disorders in children fathered by men on valproate in the three months prior to conception compared with men on other antiseizure medicines.
Any further guidance will be communicated to patients and healthcare professionals as soon as possible. As a precaution, male patients on valproate who are planning a family in the next year should talk to their healthcare professional about their treatment.
Illegal medicines worth more than £30 million seized in the UK in 2023
The MHRA, working with law enforcement partners, seized more than 15.5 million doses of illegally traded medicines with a street value of more than £30 million during 2023.
Last year’s seizures included prescription-only anti-anxiety medicines, opioids and sleeping pills and falsified and unlicensed lifestyle products such as erectile dysfunction and hair loss medications, as well as a small number of aesthetic products such as Botox and semaglutide-containing ‘weight loss’ products.
Working with partners, the MHRA also disrupted more than 12,000 websites illegally selling medical products to the public and shut down almost 3,000 social media profiles during the year.
Support and advice provided by the MHRA to online marketplaces resulted in the successful removal of more than half a million unregulated prescription medicines, over-the-counter medicines and medical devices before they could even be offered for sale to the public.
List of medicines that cannot be exported from the UK or hoarded
This document lists the medicines that cannot be exported from the UK or hoarded. The list is updated regularly.
On 30 Jan 2024 the following products were added to the list: Iodixanol (strength: all, pharmaceutical form: solution for injection); Iohexol (strength: all, pharmaceutical form: solution for injection); Nadolol (strength: 80mg, pharmaceutical form: tablets); potassium chloride/potassium bicarbonate (strength: all, pharmaceutical form: effervescent tablet); sodium dihydrogen phosphate anhydrous (strength: all, pharmaceutical form: effervescent tablet).
Two new UK Approved Bodies, delivering increased capacity for the certification of the performance and safety of medical devices,
LNE-GMED UK and Scarlet NB UK join the seven current UK Approved Bodies, increasing capacity for the certification of medical devices in the UK.
LNE-GMED UK has been designated as a UK Approved Body to assess and certify general medical devices. Scarlet NB UK has been designated with a focus on assessing and certifying software and AI as a medical device (AI/SaMD).
This comes after two of the existing UK Approved Bodies had their scope expanded, with UL International UK now designated to assess and certify general medical devices (in addition to in-vitro devices), and TÜV SÜD now designated to assess and certify active implantables (in addition to general medical devices).
Apart from the very lowest risk devices, manufacturers must apply to a UK approved body for UKCA certification. Products can only be placed on the market in England, Wales and Scotland after they have achieved certification.
Europe
European Medicines Agency (EMA)
Major update of the SME user guide
The revised user guide offers comprehensive information on the EU legislative framework for medicines, outlining requirements for the development and authorisation of medicines for human and veterinary use. It follows the chronological stages of medicine development, and has become a reference source of information for SME and academic developers, supporting them to navigate the system of medicine regulation in the EU. The new release incorporates significant updates to reflect major changes in the EU’s legal and regulatory framework for human and veterinary medicines e.g:
Veterinary Regulation: the document has been fully revised to align with the veterinary regulation
Clinical Trials Regulation (new section 4.4): provides an overview of the clinical trial regulation and Clinical Trials Information System (CTIS)
Medical Devices Regulation (new section 4.8): offers insights into the medical devices regulation for human medicines
The revision also includes many other important new sections/subsections.
Veterinary medicines: Highlights of 2023
EMA has published an overview of its key recommendations of 2023 regarding the authorisation and safety monitoring of veterinary medicines.
EMA confirms measures to minimise the risk of serious side effects with medicines containing pseudoephedrine
EMA’s human medicines committee (CHMP) endorsed the measures recommended by the Pharmacovigilance Risk Assessment Committee (PRAC) to minimise the risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) for medicines containing pseudoephedrine. PRES and RCVS are rare conditions that can involve reduced blood supply to the brain, potentially causing serious, life-threatening complications. With prompt diagnosis and treatment, symptoms of PRES and RCVS usually resolve. CHMP confirmed that medicines containing pseudoephedrine are not to be used in patients with high blood pressure that is severe or uncontrolled (not being treated or resistant to treatment) or in patients with severe acute (sudden) or chronic (long-term) kidney disease or failure.
EMA to support establishment of the African Medicines Agency
EMA has received a grant of ten million euros from the European Commission to support regulatory systems at national and regional level in Africa, and in particular for the setting up of the African Medicines Agency (AMA), in collaboration with African, European and international actors.
AMA will be a specialised agency of the African Union (AU) dedicated to improving equitable access to quality, safe and effective medical products in Africa. To date, 27 countries have ratified the AMA treaty, and more AU members are expected to complete the process in the coming months. The creation of AMA is a unique opportunity to facilitate the regulation and oversight of key medicines at continental level, promoting collaboration among African countries and regions.
New platform for collection of sales and use data of antimicrobials in animals
As of January 2024, all Member States in the European Union (EU) and European Economic Area (EEA) must submit these data annually to the Antimicrobial Sales & Use (ASU) Platform. This new obligation was introduced by the Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) as one of the measures to fight antimicrobial resistance.
The new IT system and web interface will not only streamline the submission of data for the Member States but it will also strengthen the analysis and identification of trends in antimicrobial consumption across the EU/EEA. Access to reliable data provides invaluable insights for participating countries on the impact of their measures to promote the prudent use of antimicrobials in animals, and could help to identify potential actions at national and international level to support an overall decrease of AMR.
EMA will publish annual reports showcasing the main results of the analysed data, with the first report expected in March 2025, after the first reporting cycle is concluded.
Clinical trials' transition to new EU system - one year left
All ongoing clinical trials in the EU must be transitioned to the Clinical Trials Information System (CTIS) by 31 January 2025. This date marks the end of a three-year transition period that began when the Clinical Trials Regulation (CTR) became applicable in the EU.
The authorisation and oversight of clinical trials is the responsibility of EU / EEA Member States while the European Medicines Agency is responsible for maintaining CTIS. The European Commission oversees the implementation of the Clinical Trials Regulation.
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Pharmeuropa 36.1
All new European Pharmacopoeia (Ph. Eur.) texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation.
The deadline for comments on Pharmeuropa 36.1 is 31 March 2024.
The template of Quality Overall Summary (QOS) to be submitted for Certification applications has been adapted to the current needs!
A new version of the QOS template is now available. It may be used from January 2024 and will become mandatory as of April 2024.
The QOS (eCTD Module 2) has to be provided along with an initial submission since it is essential in the review of a new CEP application. This updated template gives detailed guidance on how to address each eCTD section with a particular emphasis on the overall control strategy applied.
A short guidance for its optimal use will be available soon on the EDQM website.
CEP holders invited to comment on draft monographs published in Pharmeuropa 36.1
Holders of Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) are requested to consult the list of substances for which draft revised monographs of the European Pharmacopoeia (Ph. Eur.) have been published in Pharmeuropa 36.1. Although these draft monographs are published for public consultation only at this stage and are therefore not official standards, they will, once adopted by the European Pharmacopoeia Commission, become legally binding standards for the substances concerned. It is therefore extremely important that manufacturers and users of the substances provide feedback on these draft monographs before the commenting deadline, i.e. before 31 March 2024.
At its 177th session in November 2023, the European Pharmacopoeia Commission (EPC) approved the strategy for N-nitrosamine impurities in individual monographs.
The EPC agreed to delete the Production section covering N-nitrosamine impurities from existing individual monographs on active substances and to avoid including such statements in new monographs in the future, since the general requirement for these impurities given in revised general monograph 2034 applies to all the substances for pharmaceutical use within the given scope.
In addition, the EPC defined clear rules on when a specification for N-nitrosamine impurities should be added to the Tests section of an active substance monograph.
Where monographs on medicinal products are concerned, the EPC agreed that it was not appropriate to introduce a specification in the Tests section or a statement in the Production section, except in specific and justified cases, since the risk of N-nitrosamine formation depends to a great extent on the composition of the medicinal product and the conditions under which it is manufactured.
The N-nitrosamines section of the general monograph Pharmaceutical preparations (2619) is considered to fully address this risk
In view of this new strategy, revised versions of the five individual sartan monographs (Valsartan, Irbesartan, Candesartan cilexetil, Olmesartan medoxomil and Losartan potassium), from which the Production section referring to N-nitrosamines had been deleted, were submitted to and adopted by the EPC at the same session. The EPC considered that the information in the Production section of these individual monographs was redundant since it was already covered by the general requirement for N-nitrosamines in revised general monograph 2034.
The two other individual monographs that include a Production section (Clopamide and Dalteparin sodium) were considered to be more complex. The EPC therefore agreed to add them to the work programme of the relevant group of experts to bring them in line with the new strategy. Stakeholders will be informed in due time about the progress on these texts through the usual revision process.
Monographs that already describe a test and a limit for the control of a specific N-nitrosamine impurity (e.g. Gliclazide, Molsidomine, Indapamide and Trolamine) were not modified but will be re-examined should any new information from competent authorities become available.
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies
The EPC is currently seeking feedback from a wide range of stakeholders on the approach taken in the “MAB pilot phase” towards the concepts (including flexibility) built into mAb quality standards. The outcome of this survey will inform the final assessment of the “MAB pilot phase” and help bring this project to a close.
United States of America
The US Food and Drug Administration (USFDA)
Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin
This guidance describes the evaluation of the viral safety of biotechnology products including viral clearance and testing, and it outlines what data should be submitted in marketing applications for those products.
In this guidance, the term virus excludes nonconventional transmissible agents like those associated with mammalian prions (e.g., bovine spongiform encephalopathy & scrapie).
This guidance includes products such as cytokines, monoclonal antibodies (mAbs), and
Sub-unit vaccines produced from in vitro cell culture using recombinant DNA technologies. It also includes certain genetically engineered viral vectors and viral vector-derived products (e.g., viral vaccines, gene therapy products), provided they are amenable to viral clearance, without a negative effect on the product. These products can include viral vectors, for example, adeno-associated virus (AAV), produced using transient or stable transfected cell lines, or by infection using a recombinant virus. It also includes viral vector- derived products, for example, baculovirus-expressed virus-like particles (VLPs), protein subunits, and nanoparticle-based protein vaccines and therapeutics. AAV gene therapy vectors include those that depend on helper viruses such as herpes simplex virus or adenovirus for their production.
Cell therapies are out of the scope of this guidance; however, the principles can be used as applicable (e.g., for biological starting or raw materials).
It is no longer encouraged that materials be manufactured from hybridoma cells grown in vivo as ascites due to the contamination risk as well as to the ongoing global initiative to replace, reduce, and refine the use of animals. Where this situation exists, the principles of this guidance should be followed, including replacement of the in vivo assay by next generation sequencing (NGS).
The risk of viral contamination is a concern for all biotechnology products derived from cell lines and needs to be reduced because such contamination could have serious clinical consequences.
Three principal, complementary approaches are applied to control the potential viral contamination of biotechnology products:-
Selecting and testing cell lines and other raw materials, including media components,for the absence of undesirable infectious viruses
Assessing the capacity of the production processes to clear adventitious and endogenous viruses
Testing the product at appropriate steps of production for demonstrating the absence of contaminating infectious viruses
Revising ANDA Labeling Following Revision of the RLD Labeling Guidance for Industry
This guidance is intended to assist applicants and holders of an abbreviated new drug application (ANDA) in updating their labeling following revisions to the approved labeling of a reference listed drug (RLD). This guidance provides recommendations on identifying RLD labeling updates and submitting ANDA amendments or supplements to update generic drug labeling. This guidance revises the guidance for industry Revising ANDA Labeling Following Revision of the RLD Labeling (April 2000). After it has been finalized, this guidance will replace the April 2000 guidance. Significant changes from the 2000 version include updates to outdated details about how to obtain information on changes to RLD labeling and how to submit revised ANDA labeling to FDA.
Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products
The purpose of this guidance is to provide FDA’s expectations for, and recommendations on, use of a standardized approach for collecting and reporting race and ethnicity data in submissions including information collected and reported from clinical studies and clinical trials for FDA-regulated medical products.
Using standard terminology for race and ethnicity helps ensure that data are collected and reported consistently in submissions to FDA. This draft guidance revises the final guidance for industry and FDA staff issued on October 26, 2016.
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
PIC/S-EMA-WHO Joint Implementation Working Group
Friday, 19 January marked the inaugural kickoff meeting of the PIC/S-EMA-WHO Joint Implementation Working Group, bringing together experts from WHO, EMA, and PIC/S participating authorities. The goal is to achieve harmonized interpretation of the newly released PIC/S-EU GMP Annex 1 on Sterile Manufacturing.
6th PIC/S Expert Circle Meeting on Good Distribution Practice (GDP)
The Department of Health and the Pharmacy and Poisons Board of Hong Kong (PPBHK) hosted the 6th PIC/S Expert Circle Meeting on Good Distribution Practice (GDP) from 29 November to 1 December 2023 via Zoom. A total of 230 participants joined the meeting. The meeting included discussions on contemporary issues and latest developments in the field of GDP and supply chain integrity; consolidating lessons learnt during COVID to support uninterrupted supply chain of medicine; sharing experiences between inspectors to improve consistency among inspectors in the field of GDP; and exchanging ideas and fostering collaboration among inspectorates.
International
World Health Organisation (WHO)
WHO decision improves children’s access to safer polio vaccine
Three years after it received its Emergency Use Listing (EUL) and with 950 million doses now delivered worldwide, the novel type 2 oral polio vaccine (nOPV2), developed by a team including scientists from the UK MHRA, has been quality-assured (prequalified) by the WHO following analysis of outcomes in vaccinated populations, The nOPV2 vaccine helps to protect children from polio while lowering the risk of vaccine-derived outbreaks.
Australia – Therapeutic Goods Administration (TGA)
Repeal of Therapeutic Goods (Restricted and Prohibited Representations—Nicotine)
As part of the reforms to the regulation of vaping products, the Advertising Permission for Nicotine was repealed. This means that pharmacies can no longer advertise the availability of prescription nicotine to their customers.
Nitrosamine impurities acceptable intakes update
The TGA has published updated acceptable intake (AI) information for nitrosamine impurities in medicines consistent with recent EMA updated information. The changes include minor editorial amendments, increases to the AI limit for a nitrosamine impurity and inclusion of recently internationally determined AI limits for numerous nitrosamine impurities in medicines.
Products
Rezzayo approved in UK to treat adult patients with invasive candidiasis
MHRA has approved the medicine Rezzayo (rezafungin) to treat a fungal infection called invasive candidiasis.
The treatment is administered once a week by a drip into the vein until at least 14 days after the last day Candida is found in the bloodstream.
The active ingredient in Rezzayo, rezafungin, is an antifungal that blocks the action of the enzyme needed by fungal cells to make a molecule that strengthens their cell walls. This means the fungal cells become fragile and stops the fungus growing and spreading. It gives the body’s natural defences a chance to remove the infection.
This approval is supported by evidence from a randomised, double-blind, controlled phase 3 clinical trial involving 187 patients with invasive candidiasis.
Conferences
PHSS sterile product manufacturings and aseptic processing conference
The Belfry, Sutton Coldfield 12 & 13 March 2024. Hear from industry experts and regulators on strategies, experiences and lessons learned.
MHRA Good Pharmacovigilance Practice (GPvP) Symposium (28 February 2024)
Presentations and discussions on the key topics and compliance trends in pharmacovigilance, including:
Artificial Intelligence in PV: A Regulatory Experience
Remote Compliance Assessment Pilot
And finally…
This Update is compiled by Malcolm Holmes C.Chem. MRSC, a member of the PHSS Management Committee.
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.
