Review of Developments in GMP and the Regulation of Medicines April 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 and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
UK MHRA
Advanced therapy medicinal products: regulation and licensing in Great Britain
Disgraced company director convicted of falsifying medicine quality data.
Response to Equity in Medical Devices: Independent Review
Unsafe counterfeit anti-choking devices
EU
EMA Management Board: highlights of March 2024 meeting
Scientific Explorer - Frequently Asked Questions (FAQs)
Note on the HORIZON-JU-IHI-2024-06-two-stage funding call: Development of evidence based practical guidance for sponsors on the use of real-world data / real-world evidence.
EudraVigilance user declaration for qualified person for pharmacovigilance/responsible person for EudraVigilance
Highlights sixth EMA-EFPIA bilateral meeting
Minutes – Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG)
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Revised Regulation for the Ozone-Depleting Substances
How CEP holders can avoid the rejection of notifications
OMCL analytical procedures for determination of nitrosamine drug substance-related impurities (NDSRIs) and intermediate-related contaminants published
Stakeholder consultation – New draft technical guide on Food Contact Materials(FCM) compliance
The template of Quality Overall Summary (QOS) to be submitted for Certification applications has been adapted to the current needs.
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies.
Ireland HPRA
Close to 900,000 units of illegal medicines detained by the HPRA in 2023
USA
Q2(R2) “Validation of Analytical Procedures” and” Q14 “Analytical Procedure Development”
Annual Reportable Labeling Changes for Nonprescription Drug Products
Controlled Correspondence Related to Generic Drug Development
Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products
Handling and Retention of Bioavailability BA and Bioequivalence BE Testing Samples
International
Australia
Therapeutic Goods Administration
Recall reforms program update
Products
New antibiotic to fight infections caused by multidrug-resistant bacteria
First oral monotherapy for patients with paroxysmal nocturnal haemoglobinuria
Quizartinib approved to treat adult patients with a type of blood cancer.(MHRA)
Etrasimod approved to treat patients over the age of 16 with ulcerative colitis.(MHRA)
EU recommendations for 2024/2025 seasonal flu vaccine composition
Conferences
Simultaneous National Scientific Advice - information and training webinar (EU)
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Advanced therapy medicinal products: regulation and licensing in Great Britain
This guidance covers how to get a marketing authorisation for an Advanced Therapy Medicinal Product (ATMP) so it can be sold and/or supplied in Great Britain. The guidance was first published on 26 January 2015 and has since been recently updated on 19 March 2024 providing updated guidance and an ATMP Flowchart.
Disgraced company director convicted of falsifying medicine quality data.
A company director and his pharmaceutical manufacturing company were sentenced in court after pleading guilty to two charges of falsifying data that supported the shelf life of a medicine, adversely affecting its quality in order to obtain a licence to sell the medicine in the UK.
This sentencing concludes the UK’s first successful prosecution of a manufacturer for knowingly providing falsified data to the MHRA in order to obtain a Marketing Authorisation.
The former director was sentenced to eight and seven months on two counts, to run concurrently, both suspended for 18 months The former director and the company were both individually fined £50,000, having previously paid a confiscation order of £1,075,589.88, reflecting the company’s profit from the crime. The company was also ordered to pay prosecution costs of £82,262.20.
Response to Equity in Medical Devices: Independent Review
The MHRA is fully committed to ensuring equitable access to safe, effective, and high-quality medical devices for all individuals who use them. It acknowledges that more needs to be done to address inequities in relation to the regulation of medical devices. It is committed to working collaboratively with Government, other regulatory bodies, healthcare professionals, and patient groups to address these issues effectively
MHRA is taking forward the following measures to strengthen the regulatory environment for medical devices and promote equity:
Working towards providing strengthened guidance to developers and manufacturers on improving diversity in testing, investigating and development of medical devices
Engaging in Software and AI as a Medical Device Change Programme, to ensure device regulation is fit for purpose, taking into account the diversity of users of AI and other software as a medical device and diagnostics
Continuing to strengthen its vigilance role, as specified in Baroness Cumberlege’s Independent Medicines and Medical Devices Safety review by listening to and engaging with patients and the public.
Unsafe counterfeit anti-choking devices
Thousands of counterfeit or unbranded copies of LifeVac anti-choking devices are being sold across the UK. The public is reminded to check their product carefully against the images in MHRA guidance to identify whether it is a counterfeit.
MHRA is warning the public not to buy counterfeit or unbranded anti-choking devices as they do not comply with device regulations and could cause harm.
It is estimated that over 10,000 counterfeit or unbranded anti-choking devices, also known as airway clearance devices, choking rescue devices or emergency first aid devices, have been purchased by the public within the last two years based on listings found across online marketplaces like Amazon and eBay, and drop-shipping websites.
There are currently two anti-choking device brands, LifeVac and Dechoker, which have a valid UKCA or CE mark and are registered with the MHRA to be used after Basic Life Support protocols have been attempted and failed. Use of a counterfeit or unbranded anti-choking device carries a significant risk of failure to resolve the blockage and may worsen the situation by pushing obstructions further down the airway passage.
Europe
European Medicines Agency (EMA)
EMA Management Board: highlights of March 2024 meeting
Topics covered in the outcomes of the EMA Management Board meeting include:-
EMA annual report 2023
Update on the new Health Technology Assessment Regulation
Clinical trials in the EU
EMA report on stakeholder engagement activities 2022-2023
Monitoring of EMA’s independence policies
Update on new fee regulation
Scientific Explorer - Frequently Asked Questions (FAQs)
Scientific Explorer is a search engine to aid European Medicines Regulatory Network’s (EMRN) scientific staff (who have access to IRIS) to find information effectively, and incorporates AI techniques. The launch of Scientific Explorer marks an important milestone in harnessing the capabilities of AI to help extract information from the Network’s knowledge sources.
Users of the tool are from EMA scientific committee members, EMA staff or staff from national competent authorities (NCAs) who are entitled to access the IRIS platform that handles scientific advice data. Scientific Explorer is for European Medicines Regulatory Network use only.
[A Big Data related development for use by Regulators only -but, of which our readers should be aware.MBH]
Note on the HORIZON-JU-IHI-2024-06-two-stage funding call: Development of evidence based practical guidance for sponsors on the use of real-world data / real-world evidence.
This note provides organisations planning to submit a proposal to the HORIZON-JU-IHI-2024-06-two-stage call with information to be considered concerning a potential involvement of the EMA in their proposal and consortium.
The EMA and the European Medicines Regulatory network, overseen by the EMA-HMA Big Data Steering Group, are working towards a sustainable framework that enables the use and establishes the value of RWE in decision-making across the entire medicinal product lifecycle. Therefore, the EMA considers that it might participate in decisions on the orientation of the proposed work programme, development of research protocols, discussion and dissemination of results. This role would go beyond participation in an advisory board and may require membership in the steering group(s) or in relevant work package(s), depending on the proposal and workload. The EMA will however not lead, manage, or coordinate a work package, but may provide expertise where appropriate.
Applicants can propose EMA’s involvement in their documentation submitted with their proposal. For the applicant consortium invited to the second stage, EMA can be requested to be involved and will take a decision in line with the provisions described
EudraVigilance user declaration for qualified person for pharmacovigilance/responsible person for EudraVigilance
This document was updated as of 29 Feb 2024
Highlights sixth EMA-EFPIA bilateral meeting
The bilateral meeting was an opportunity to discuss the challenges and opportunities for the
pharmaceutical ecosystem. The value of having constant dialogue and engagement enabling both parties to understand each other perspectives was recognised.
Topics covered were:-
The pharmaceutical legislation review and its implications for the EU regulatory framework
Interface between medicines and chemical/food/environmental agenda
Implementation of the HTA regulation with a main focus on EMA-HTA interactions
EU Critical Medicines List, Drug Shortages Monitoring Platform and European Medicines Verification System
EFPIA position on interface between medical device and pharmaceutical legislation
Minutes – Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG)
Minutes from the 29Jan 24 meeting have now been published
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Revised Regulation for the Ozone-Depleting Substances
The rules governing the placing on the market and use of ozone-depleting substances (ODSs) for essential laboratory and analytical uses have now changed.
Under the new regulation, standards shipped to a location within the European Union no longer need to be registered in the labODS registry.
There is no change to the procedure for shipments outside the European Union.
Two reference standards of the EDQM are affected by this change
In all cases, these reference standards supplied by the EDQM must be used exclusively for essential laboratory and analytical uses (i.e. for analytical uses in conjunction with the texts published in the European Pharmacopoeia).
How CEP holders can avoid the rejection of notifications
In order to facilitate the acceptance of proposed changes in a timely manner, CEP holders are reminded that the EDQM Guideline on requirements for revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs lists different notifications and associated conditions, and that any change not classified as a notification or a major change should be classified as a minor change by default (with the exception of editorial changes for which specific guidance is given in the policy document). If the change cannot be classified by the document and specifically as a notification, a minor revision (by default) should be submitted.
Any submission of a notification which includes changes not classifiable as a notification will be rejected and the changes will then need to be resubmitted using the correct classification (with associated documentation and fee).
OMCL analytical procedures for determination of nitrosamine drug substance-related impurities (NDSRIs) and intermediate-related contaminants published
Six additional procedures have now been published on the EDQM website. In one case (NTTP in sitagliptin tablets and in sitagliptin/metformin tablets), the contaminant derives from an active pharmaceutical ingredient intermediate.
The target molecules are:
7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (NTTP) in sitagliptin and sitagliptin/metformin tablets;
N-nitroso ramipril in ramipril tablets;
N-nitroso fluoxetine in fluoxetine tablets;
N-nitroso sertraline in sertraline preparations;
N-nitroso duloxetine in duloxetine preparations; and
N-nitroso hydrochlorothiazide in various preparations.
The analytical techniques used to detect these contaminants are GC-MS/MS in the case of NTTP and LC-MS/MS in the other five cases.
Stakeholder consultation – New draft technical guide on Food Contact Materials (FCM) compliance
A new draft technical guide on documentation supporting compliance and safety of food contact materials and articles is now open for comment. The EDQM invites all parties concerned to provide their valuable input before the deadline of 30 April 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.
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies.
In 2014, the European Pharmacopoeia Commission (EPC) launched a pilot phase on setting public standards for therapeutic monoclonal antibodies (mAbs) (“MAB pilot phase”). This pilot phase was intended to explore the feasibility of establishing individual monographs for multi-source mAbs, as well as the applicability of general concepts to standardisation of quality attributes common to classes of mAbs. 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.
Ireland
The Health Products Regulatory Authority (HPRA)
Close to 900,000 units of illegal medicines detained by the HPRA in 2023
HPRA has released its annual enforcement data which shows that it detained 874,945 dosage units of falsified and other illegal medicines in 2023.
Announcing the figures, the HPRA warned of the serious health dangers posed by sourcing prescription medicines online and from unauthorised sources. It states that the supply of these products into and within Ireland is illegal and stresses that consumers can have no guarantees about the safety or quality of prescription medicines they are seeking to buy outside of the regulated pharmacy setting.
In the 12 months of 2023, the most significant categories of illegal products detained included sedatives (34%), anabolic steroids (29%), erectile dysfunction medicines (10%), analgesics (5%), and Stimulants (3%).
United States of America
The US Food and Drug Administration (USFDA)
Q2(R2) “Validation of Analytical Procedures” and” Q14 “Analytical Procedure Development”
FDA or Agency is announcing the availability of final guidances for industry entitled “Q2(R2) Validation of Analytical Procedures” and “Q14 Analytical Procedure Development.” The guidances were prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidance entitled “Q2(R2) Validation of Analytical Procedures” provides a general framework for the principles of analytical procedure validation, including validation principles that cover the analytical use of spectroscopic data. The guidance entitled “Q14 Analytical Procedure Development” provides harmonized guidance on scientific approaches for analytical procedure development and describes principles to facilitate more efficient, science-based, and risk-based postapproval change management. The guidances are intended to facilitate regulatory evaluations and potential flexibility in postapproval change management of analytical procedures when scientifically justified. The guidances replace the draft guidances “Q2(R2) Validation of Analytical Procedures” and “Q14 Analytical Procedure Development” issued on August 29, 2022.
Annual Reportable Labeling Changes for Nonprescription Drug Products
FDA, is announcing the availability of a draft guidance for industry entitled “Annual Reportable Labeling Changes for NDAs and ANDAs for Nonprescription Drug Products.” This draft guidance provides recommendations to applicants of approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for nonprescription drug products on documenting minor labeling changes in the next annual report and provides examples of minor labeling changes that may be submitted in an annual report. FDA anticipates that these recommendations may assist industry in understanding the circumstances in which it would be appropriate to document minor changes in the applicant’s next annual report rather than submitting a prior approval supplement (PAS), or “changes being effected” supplement (CBE), thereby reducing burden on both industry and FDA.
Controlled Correspondence Related to Generic Drug Development
This guidance provides information regarding the process by which generic drug manufacturers and related industry can submit controlled correspondence to FDA requesting information related to generic drug development and the Agency’s process for providing communications related to such correspondence. This guidance also describes the process by which generic drug manufacturers and related industry can submit requests to clarify ambiguities in FDA’s controlled correspondence response and the Agency’s process for responding to those requests. This guidance finalizes the draft guidance of the same title issued on December 22, 2022.
Real-World Evidence: Considerations Regarding Non-Interventional Studies for Drug and Biological Products
FDA is issuing this draft guidance as part of a series of guidance documents under its Real-World Evidence (RWE) Program and to satisfy, in part, a mandate under the Federal Food, Drug, and Cosmetic Act (FD&C Act) to issue guidance about the use of RWE in regulatory decision-making. The draft guidance provides recommendations to sponsors who are considering submitting a non-interventional study, also referred to as an observational study, to FDA to contribute to a demonstration of substantial evidence of effectiveness and/or evidence of safety of a drug. This draft guidance was developed in response to stakeholders’ growing interest in the potential use of non-interventional studies to contribute to a demonstration of the effectiveness or safety of a drug.
Handling and Retention of Bioavailability BA and Bioequivalence BE Testing Samples
This guidance is intended to provide recommendations for study sponsors and/or drug manufacturers, contract research organizations (CROs), site management organizations (SMOs), clinical investigators, and independent third parties regarding the procedure for handling reserve samples from relevant bioavailability (BA) and bioequivalence (BE) studies, as required by 21 CFR 320.38 and 320.63. The guidance highlights (1) how the test article and reference standard for BA and BE studies should be distributed to the testing facilities, (2) how testing facilities should randomly select samples for testing and material to maintain as reserve samples, and (3) how the reserve samples should be retained.
International
Australia
Recall reforms program update
The second phase of the Recall Reforms is now being implemented. Updated processes will reduce regulatory burden for sponsors while maintaining a strong emphasis on public safety. The reforms include a simplified and more flexible reporting process, increased stakeholder communication for the ‘Early Advice’ process and improvements to recall documentation and guidance.
Products
New antibiotic to fight infections caused by multidrug-resistant bacteria
EMA has recommended granting a marketing authorisation in the European Union (EU) for Emblaveo (aztreonam-avibactam), indicated for the treatment of complicated intra-abdominal and urinary tract infections, hospital-acquired pneumonia and infections caused by certain types of bacteria (aerobic Gram-negative) where treatment options are limited.
Infections due to Gram-negative bacteria that are resistant to many currently available antibiotics are a serious public health problem since patients have limited or sometimes no treatment options. Infections due to multidrug-resistant bacteria are estimated to cause 35,000 deaths in the EU every year.
Emblaveo is a fixed-dose combination of two active substances, aztreonam and avibactam. Aztreonam is already authorised for use in the EU on its own and avibactam is authorised for use in combination with another antibiotic (ceftazidime). Aztreonam is an antibiotic that belongs to the group ‘beta-lactams’. It works by attaching to proteins on the surface of the bacteria. This prevents the bacteria from building their cell walls, which kills them.
Avibactam blocks the action of many of the bacterial enzymes called beta-lactamases. These enzymes enable bacteria to break down beta-lactam antibiotics, such as aztreonam, making them resistant to the antibiotic’s action. By blocking these enzymes, avibactam restores the activity of aztreonam against aztreonam-resistant bacteria.
Emblaveo will be available to be given by infusion into a vein.
EMA’s human medicines committee (CHMP) considered that the benefits of Emblaveo outweigh its risks for patients with infections caused by Gram-negative bacteria when they have few or no therapeutic options to fight the disease.
Emblaveo was evaluated under EMA's accelerated assessment mechanism because it is considered to be of major public health interest.
First oral monotherapy for patients with paroxysmal nocturnal haemoglobinuria
EMA has recommended granting a marketing authorisation in the European Union (EU) for Fabhalta (iptacopan), an oral treatment for adults with paroxysmal nocturnal haemoglobinuria (PNH) who have haemolytic anaemia. PNH is a rare genetic disorder that causes the premature breakdown of red blood cells (haemolytic anaemia) by the immune system, and is potentially life-threatening.
The active substance of Fabhalta is iptacopan, a proximal complement inhibitor. Complement inhibitors are a type of immunotherapy used in the treatment of many inflammatory conditions that could be caused by deficiencies of the complement system, a part of the body's immune system. Iptacopan targets Factor B to selectively inhibit the alternative complement pathway and prevent the destruction of red blood cells within blood vessels (intravascular haemolysis) and in the liver and spleen (extravascular haemolysis).
EMA’s recommendation is based on the results of two phase III trials.
The opinion adopted by the CHMP is an intermediary step on Fabhalta’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation.
Quizartinib approved to treat adult patients with a type of blood cancer
UK MHRA has approved the medicine quizartinib (Vanflyta) to be used alongside chemotherapy as first line treatment for adults who have acute myeloid leukaemia (AML). AML is a type of blood cancer, which progresses quickly and aggressively, and requires immediate treatment. Each year in the UK around 3,100 people are diagnosed with AML, which can affect the different types of blood cells in the bone marrow, and can lead to bleeding, anaemia and infections.
Treatment is taken orally, once a day at around the same time for two weeks, during each cycle of chemotherapy. The prescribing doctor will determine the dose of quizartinib that should be taken and for how long. Quizartinib blocks the action of tyrosine kinases, the proteins responsible for the body producing large numbers of abnormal bone marrow cells that do not mature to become healthy cells.
This regulatory approval (granted to Daiichi Sankyo UK Ltd.) is supported by evidence from a randomised, double-blind, placebo-controlled, phase 3 clinical trial involving 539 adult patients (aged between 18 and 75 years) newly diagnosed with FLT3-ITD positive AML.
Etrasimod approved to treat patients over the age of 16 with ulcerative colitis
UK MHRA has approved the medicine etrasimod (Velsipity) to treat people with moderately to severely active ulcerative colitis. Ulcerative colitis is a long-term condition where the colon and rectum become inflamed. Small ulcers can develop on the colon’s lining and can bleed and produce pus.
Etrasimod is a long-term prescription medicine and treatment should only be started under the supervision of a doctor who is experienced in treating ulcerative colitis.
This regulatory approval is supported by evidence from two randomised, double-blind, placebo-controlled clinical studies (ELEVATE UC 52 and ELEVATE UC 12) involving 743 patients aged 16 years and over for whom standard treatment or other treatments did not work well enough or could not be used.
EU recommendations for 2024/2025 seasonal flu vaccine composition
EMA has issued recommendations for the influenza virus strains that vaccine manufacturers should include in vaccines for the prevention of seasonal influenza from autumn 2024.
EMA’s Emergency Task Force (ETF) has issued a statement recommending a transition from quadrivalent to trivalent vaccines that do not include the B/Yamagata component. Currently, most authorised influenza vaccines are quadrivalent, which means that they are formulated to protect against the four main strains of influenza responsible for seasonal flu, A(H1N1)pdm09 and A(H3N2), B/Victoria and B/Yamagata. However, the B/Yamagata strain of the influenza B virus has not been detected in circulation since March 2020. This is thought to be due in part to the public health measures put in place to limit the spread of COVID-19 during the pandemic. The ETF recommends that this strain should ideally be removed from all live-attenuated vaccines from the 2024/2025 season. In the interest of guaranteeing vaccine supplies for the coming vaccination campaign, the transition to a trivalent composition for all other influenza vaccines should be completed for the 2025/2026 season.
[Interesting comment re the possible knock-on effect of health measures put in place during the COVID -19 pandemic. MBH]
Conferences
Simultaneous National Scientific Advice - information and training webinar (EU)
The EU Innovation Network, in conjunction with ACT EU, is organising an information and training webinar on Simultaneous National Scientific Advice (SNSA) to be held on 19th April 2024.
The objectives of the webinar are to:
provide information on the ongoing SNSA pilot, including the rationale behind this initiative and experience to date;
outline the circumstances in which SNSA could be used, including some case studies;
summarise the optimised procedure for phase 2 of the SNSA pilot;
highlight the benefits for applicants;
answer questions and invite feedback from stakeholders in relation to SNSA.
This EMA-hosted webinar anticipates a broad representation of stakeholders who may benefit from using SNSA including pharmaceutical companies, SMEs, and non-commercial or academic researchers and developers, funding bodies, etc.
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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