top of page

Review of Developments in GMP and the Regulation of Medicines January 2024




Vol 29.1A
.pdf
Download PDF • 239KB


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 ICMRA regulatory authorities.

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

UK MHRA

  • Innovate - UK’s first-of-its-kind initiative to fund new Regulatory Science and Innovation Networks

  • Manchester family locked up for illegal sale and supply of unlicensed medicines worth £1.5m

  • GMP & GDP Certificates: Validity Period Extended – MHRA Blog

  • International Recognition Procedure

EU

  • Artificial intelligence workplan to guide use of AI in medicines regulation

  • Midterm report on 2025 network strategy highlights good progress during critical period of the pandemic

  • Guideline on the evaluation of the benefit-risk balance of veterinary medicinal products


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

  • EU Parliament and Council’s political agreement on enhanced safety and quality for substances of human origin

  • Implementation of the European Pharmacopoeia Supplement 11.5 – Notification for CEP holders

  • New Ph. Eur general chapter on comparability of alternative analytical procedures

  • General chapters on powder characterisation techniques modernised

  • Q & A on implementation of Ph.Eur. Medicinal Product Monographs

  • First version of the Union list of critical medicines agreed to help avoid potential shortages in the EU


Ireland

Health Products Regulatory Authority (HPRA)  

  • Questions and answers on the Windsor Framework


USA


  • What You Should Know about Eye Drops

  • Quality Considerations for Topical Ophthalmic Drug Products

  • Reformulating Drug Products That Contain Carbomers Manufactured With Benzene

  • Interim Policies on Compounding Using Bulk Drug Substances Under Section 503A and 503B of the FD&C Act

  • Advanced Manufacturing Technologies Designation Program

  • Development of Monoclonal Antibody Products Targeting SARS-CoV-2 for Emergency Use Authorization  


International

International Coalition of Medicines Regulatory Authorities (ICMRA)

  • Global regulators strengthen efforts to ensure continuous availability of safe and high-quality medicines

Products

  • FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain

  • New treatment for young children with parasitic disease schistosomiasis

  • EMA confirms recommendation for non-renewal of authorisation of multiple myeloma medicine Blenrep


Documents

  • Follow up reply to MEPs regarding mRNA COVID -19 vaccines


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS

UK

MHRA

Innovate - UK’s first-of-its-kind initiative to fund new Regulatory Science and Innovation Networks   

Applications are now open for academic institutions wishing to bid for funding to collaborate with others to establish new Regulatory Science and Innovation Networks (RSINs) in innovative sectors.

In a drive to proactively deliver agile and robust regulatory pathways and guidance to support the innovators of today and tomorrow, the MHRA has helped shape the design of this programme with partners across government, which will enable research informing the future of UK regulatory practice.  

Manchester family locked up for illegal sale and supply of unlicensed medicines worth £1.5m

The three men pleaded guilty to illegally making these medicines available online on three different websites for the public to purchase without prescriptions. As well as the controlled medicines, over half a million erectile dysfunction, slimming and herbal tablets were also found, with an estimated value of approximately £500k.

Denis Sutherland was sentenced to three years in jail, while David Sutherland and Cleave Lewis were sentenced to a year in jail, suspended for two years, with 200 hours of unpaid community work each.  

GMP & GDP Certificates: Validity Period Extended – MHRA Blog

Following the end of the COVID-19 public health emergency, on-site GMP and GDP inspections were restarted after being postponed or carried out remotely during the pandemic.  A number of postponed inspections still need to be carried out and will be completed as soon as possible. The validity of GMP and GDP certificates has currently been extended until the end of 2023.  The MHRA (in consultation with our international partners) has decided to continue the extension of the validity date until 2024 or until the conclusion of the next inspection, whichever comes first, except where clarifying remarks in the certificate state otherwise.

International Recognition Procedure

As of 20 Dec.2023 a recording of the 'MHRA International Recognition Webinar November 2023' has been added to this guidance.


Europe

European Health Union

Artificial intelligence workplan to guide use of AI in medicines regulation

EMA and the Heads of Medicines Agencies (HMAs) have published an artificial intelligence (AI) workplan to 2028, setting out a collaborative and coordinated strategy to maximise the benefits of AI to stakeholders while managing the risks.

The workplan will help the European medicines regulatory network (EMRN) to embrace the opportunities of AI for personal productivity, automating processes and systems, increasing insights into data and supporting more robust decision-making to benefit public and animal health.

The field of AI is developing swiftly. Pharmaceutical companies increasingly use AI-powered tools in research, development and monitoring of medicines. National competent authorities are responding to the new opportunities and challenges by starting to use and develop AI tools.

The workplan focuses on four key dimensions:

  • Guidance, policy and product support

  • AI tools and technology

  • Collaboration and training

  • Experimentation

As AI technology is fast evolving, including the ethical and policy aspects related to it, the BDSG will regularly update the workplan. Regulators, medicine developers, academics, patient organisations and other interested parties will be informed and engaged throughout the implementation of the plan.

EMA Management Board

EMA has published the highlights of December 2023 meeting

Midterm report on 2025 network strategy highlights good progress during critical period of the pandemic

The midterm report of the European Medicines Agencies Network Strategy (EMANS) finds the pandemic strengthened the network and supported transformative change in the European system across key strategic areas. The European medicines regulatory network is on track to meet its strategic goals and objectives covering availability and accessibility of medicines; data analytics, digital tools, and digital transformation; innovation; antimicrobial resistance and other emerging health threats; supply-chain challenges; sustainability of the network and operational excellence, according to the midterm report of the network strategy.

The EMANS sets out how the network continues to enable the supply of safe and effective medicines, adapting to new developments in science, medicine, digital technologies, globalisation and emerging health threats. It was built following an extensive period of outreach, analysis, and consultation with EMA’s scientific committees, stakeholders, and EU regulatory partners through a public consultation before its final publication in December 2020.

Guideline on the evaluation of the benefit-risk balance of veterinary medicinal products  

This guideline was developed to facilitate the methodology for benefit-risk evaluations of the different pre-and post-authorisation applications of veterinary medicinal products, to provide a systematic approach, hence improving the consistency and transparency of decisions taken at CVMP level.

In light of the implementation of Regulation (EU) 2019/6 and experience gained over the years, the CVMP has revised the guideline.

The guideline is intended to provide details on the conduct of the benefit-risk evaluation, to give

guidance on when and how to perform a benefit-risk evaluation, and to be a basis for the elaboration of all assessment documents that include a section on the evaluation of the benefit-risk balance. It is addressed to those performing a benefit-risk evaluation of veterinary medicinal products, which includes regulators and applicants or marketing authorisation holders of a veterinary medicinal product.

Q&A on implementation of Ph.Eur. Medicinal Product Monographs

This is a new (30 Oct 2023) 11 point Q&A.

[Essential reading. MBH]  

First version of the Union list of critical medicines agreed to help avoid potential shortages in the EU

The European Commission (EC), the Heads of Medicines Agencies (HMA) and EMA have published the first version of the Union list of critical medicines. It contains more than 200 active substances of medicines for human use considered critical for healthcare systems across the EU/EEA, for which continuity of supply is a priority and shortages should be avoided. The European medicines regulatory network will prioritise critical medicines for EU-wide actions to strengthen their supply chain.

The list is an important tool to support the EU’s efforts in ensuring supply security and preventing shortages of critical medicines. Inclusion in the list does not mean that the medicine is likely to experience a shortage in the near future. It means that the prevention of shortages is particularly important as a shortage could cause significant harm to patients and pose important challenges to health systems. A medicine is considered critical if it is used in serious diseases and cannot be easily replaced by other medicines, for example in case of a shortage. It is included in the Union list of critical medicines if it meets certain criteria, including being critical in more than one third of EU/EEA countries.

The list contains active substances covering a wide range of therapeutic areas, and includes vaccines and medicines for rare diseases. It reflects the outcome of the review of 600 active substances taken from six national lists of critical medicines. The Union list will be expanded in 2024 and will then be updated every year.


Ireland

Health Products Regulatory Authority (HPRA)

Questions and answers on the Windsor Framework

HPRA has published a Q&A document relating to the impact of the Windsor Framework on the regulation of human medicines. The document is based on questions the HPRA has received from companies.



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

EU Parliament and Council’s political agreement on enhanced safety and quality for substances of human origin

EDQM welcomes the recent provisional agreement reached between the European Parliament and the Council of the European Union (EU) on the draft regulation on blood, tissues and cells. This marks a pivotal step towards harmonising quality and safety standards for substances of human origin (SoHO) across the EU. This provisional agreement will now have to be endorsed by the Council and the Parliament.

The new regulation, whose broad scope covers all SoHO, including faecal microbiota and human breast milk, will enhance the protection of both donors and recipients. With this in mind, it will further build on existing expertise, notably that of the European Centre for Disease Prevention and Control (ECDC) and the EDQM, both of which have extensive experience in the development of technical guidelines that keep pace with the latest scientific developments.

Implementation of the European Pharmacopoeia Supplement 11.5 – Notification for CEP holders

Supplement 11.5 of the European Pharmacopoeia (Ph. Eur.) is now available. Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are invited to update their applications according to the revised monographs that will be implemented on 1 July 2024.

New Ph. Eur general chapter on comparability of alternative analytical procedures

This new general chapter describes how to demonstrate the comparability of an alternative analytical procedure to a pharmacopoeial analytical procedure, in line with the requirement laid down in section 1.1.2.5 of the Ph. Eur. General Notices, which states: “… alternative analytical procedures may be used for control purposes, provided that they enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official procedures were used.”

General chapter 5.27. Comparability of alternative analytical procedures, does not introduce any new requirements, but is published for information. The text provides practical guidance on how users who wish to rely on an alternative analytical procedure instead of the pharmacopoeial procedure for their testing strategy can demonstrate comparability and indicates that this comparability must be maintained over the lifecycle of both analytical procedures.

The EDQM will hold a webinar on 17 January 2024 to present the new general chapter to its stakeholders in detail and provide an opportunity to answer any related questions.

General chapters on powder characterisation techniques modernised   

EDQM is proud to highlight the remarkable progress made in 2023 on five general chapters of the Ph. Eur) that cover procedures for powder characterisation. The three revised and two newly elaborated texts add further state-of-the-art methods to the Ph. Eur.

Four of the general chapters have just been published in Ph. Eur. Supplement 11.5 with an implementation date of 1 July 2024. The four chapters are:

  • Particle size analysis by dynamic light scattering (2.9.50)

  • Bulk density of powders (2.9.34)

  • Powder flow (2.9.36),

  • Density of solids (2.2.42)

Particle size and shape determination by image analysis (2.9.48) was already published in Ph. Eur. Supplement 11.3 and is to be implemented by stakeholders as of 1 January 2024.

United States of America

The US Food and Drug Administration (USFDA)

What You Should Know about Eye Drops

Ophthalmic drug products, such as eye drops, pose a heightened risk of harm to users because drugs applied to the eyes bypass some of the body’s natural defenses. Any drug used in the eyes must be sterile to reduce the risk of infection. Eye drops are available by prescription or sold as over-the-counter (OTC) products.

There have been several recent safety recalls related to OTC eye drop products. These recalls resulted from various safety concerns, including infections, partial loss of vision, and blindness. The recalls were due to product contamination risks.

FDA specifically notes that patients should not use ophthalmic products that:

  • Are marketed as OTC products to treat serious eye conditions such as glaucoma, cataracts, retinopathy or macular degeneration. There are no OTC treatments for these conditions.

  • Are labeled as homeopathic, as these products should not be marketed.

Quality Considerations for Topical Ophthalmic Drug Products

This draft guidance discusses certain quality considerations for ophthalmic drug products (i.e., gels, ointments, creams, and liquid formulations such as solutions, suspensions, and emulsions) intended for topical delivery in and around the eye. Specifically, the guidance discusses:

  • Microbiological considerations.

  • Approaches to evaluating visible particulate matter, extractables and leachables, and impurities and degradation products.

  • Use of in vitro drug release/dissolution testing as an optional quality control strategy for certain ophthalmic dosage forms.

  • Recommendations for design, delivery, and dispensing features of container closure systems (CCSs).

  • Recommendations for stability studies.

Reformulating Drug Products That Contain Carbomers Manufactured With Benzene  

The purpose of this guidance is to provide recommendations for applicants and manufacturers on what tests should be performed and what documentation should be submitted or available to FDA to support the reformulation of drug products that use carbomers manufactured with benzene. Certain United States Pharmacopeia (USP) carbomer monographs currently allow for unacceptable levels of benzene, which raises safety concerns. FDA has requested that the USP omit (or remove) these monographs, and applicants and manufacturers may need to reformulate their drug products to avoid using these carbomers. This guidance provides recommendations for testing and documentation related to reformulation, taking into consideration the various routes of administration and dosage forms of affected drug products. For application holders, this guidance also recommends appropriate submission types to notify the Agency of such changes.

The recommendations in this guidance are consistent with the International Council for Harmonisation (ICH) guidance for industry Q3C.

FDA is implementing this guidance without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate FDA made this determination because benzene is a known human carcinogen. By providing recommendations on how applicants and manufacturers can reformulate certain drug products, the Agency seeks to facilitate the transition away from using carbomers manufactured with high levels of benzene.

Interim Policies on Compounding Using Bulk Drug Substances Under Section 503A and 503B of the FD&C Act

FDA has published these two interim guidances to describe FDA’s interim policy regarding the use of bulk drug substances in compounding by outsourcing facilities while FDA develops the list of bulk drug substances that outsourcing facilities can use in compounding under the applicable section of the FD&C Act.

Section 503A of the FD&C Act describes the conditions that must be satisfied for human drug products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, or by a licensed physician, to be exempt from three sections of the FD&C Act.

Section 503B of the FD&C Act describes the conditions that must be satisfied for human drug products compounded by an outsourcing facility to be exempt from the three sections of the FD&C Act

Advanced Manufacturing Technologies Designation Program

FDA encourages the early adoption of advanced manufacturing technologies (AMTs) that have the potential to benefit patients by improving manufacturing and supply dependability and optimizing development time of drug and biological products. These technologies can be integral to ensuring quality and supporting a robust supply of drugs that are life-supporting, life-sustaining, of critical importance to providing healthcare, or in shortage. AMTs can directly improve product quality through higher capability manufacturing designs and enhanced controls (e.g., leading to fewer human errors). This draft guidance provides recommendations to persons and organizations interested in participating in FDA’s Advanced Manufacturing Technologies Designation Program, which is intended to facilitate the development of drugs, including biological products, manufactured using an AMT that has been designated as such under the program.

Development of Monoclonal Antibody Products Targeting SARS-CoV-2 for Emergency Use Authorization 

This final guidance for immediate use provides recommendations to sponsors on the development of monoclonal antibody products targeting SARS-CoV-2 intended for the prevention or treatment of COVID-19, including addressing the impact of emerging variants. The recommendations focus on the data and information that may be used to support a request for emergency use authorization (EUA)This guidance supersedes the prev0us version issued on February 22, 2021.


International 

International Coalition of Medicines Regulatory Authorities (ICMRA)

Global regulators strengthen efforts to ensure continuous availability of safe and high-quality medicines

Close collaboration between medicines regulators worldwide is paving the way towards the development of a global Pharmaceutical Quality Knowledge Management System (PQ KMS). The goal is to ensure patients can benefit from a continuous supply of life-saving medicines in a world where changing manufacturing processes, technological innovations and complex supply chains can, among other factors, affect the availability of medicines.

 

Products

FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain

FDA continues to investigate counterfeit Ozempic (semaglutide) injection 1 milligram (mg) in the legitimate U.S. drug supply chain and has seized thousands of units of the product. The agency advises wholesalers, retail pharmacies, health care practitioners and patients to check the product they have received and not distribute, use, or sell products labeled with lot number NAR0074 and serial number 430834149057 FDA and Novo Nordisk (manufacturer of Ozempic) are testing the seized products and do not yet have information about the drugs’ identity, quality, or safety.

Additionally, analysis found the needles from the samples are counterfeit. Accordingly, the sterility of the needles cannot be confirmed, which presents an increased risk of infection for patients who use the counterfeit products. Based on analyses completed to date, other confirmed counterfeit components within the seized products are the pen label, accompanying health care professional and patient information, and carton.

New treatment for young children with parasitic disease schistosomiasis

EMA’s CHMP has adopted a positive scientific opinion for Arpraziquantel used to treat schistosomiasis in young children aged 3 months to 6 years.

Schistosomiasis is a neglected tropical disease caused by blood flukes (trematode worms) that can remain in the body for many years and cause damage to organs such as the bladder, the kidneys and the liver. The parasite lives in fresh water in tropical and subtropical regions. The disease mostly affects communities without access to safe drinking water and adequate sanitation. It is found throughout Africa, and also in parts of South America, the Caribbean, the Middle East and Asia.

Arpraziquantel is the first medicine formulated to meet the needs of preschool-aged children. It is derived from praziquantel, the standard treatment for schistosomiasis developed in the 1970s.The medicine will be available as 150 mg dispersible tablet. It is approved for children weighing at least 5 kg and it is to be taken fully dispersed in water using a cup or a syringe. The medicine has a taste acceptable for young children and withstands the hot environment of tropical climate.

EMA confirms recommendation for non-renewal of authorisation of multiple myeloma medicine Blenrep

CHMP has confirmed its initial recommendation to not renew the conditional marketing authorisation for Blenrep (belantamab mafodotin) because recent data did not confirm its effectiveness; the benefits of Blenrep are therefore considered to no longer outweigh its risks. Blenrep was authorised for adults who had received at least four previous treatments and whose disease did not respond to certain other types of treatment and had worsened since the last treatment.

During a re-examination requested by the company that markets the medicine, the CHMP re-assessed the results from the DREAMM-3 study, which compared Blenrep with pomalidomide plus low-dose dexamethasone. During the re-examination, the CHMP consulted a scientific advisory group (SAG) comprising of experts in the treatment of cancer. These experts were of the view that the DREAMM-3 study did not confirm the effectiveness of Blenrep. However, the majority of SAG experts were also of the opinion that Blenrep could be a treatment option for some patients for whom other treatments were not suitable.

In reaching its final opinion, the CHMP considered the views of the SAG, the results of the DREAMM-3 study which failed to confirm the effectiveness of Blenrep, and the medicine’s safety profile.

EMA will now send the CHMP’s opinion to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.

EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna 

EMA’s human medicines committee (CHMP) has recommended not renewing the marketing authorisation for Translarna (ataluren), a medicine for treating patients with Duchenne muscular dystrophy whose disease is caused by a type of genetic defect called a ‘nonsense mutation’ in the dystrophin gene and who are able to walk. 

The recommendation follows the full re-evaluation of the benefits and risks of the medicine during the renewal of its marketing authorisation, including results of a new study which failed to confirm Translarna's effectiveness. 

Because Translarna was meant to address an unmet medical need for a serious disease, it received a conditional marketing authorisation in July 2014.The CHMP considered that the data now available on Translarna are comprehensive. The committee concluded that Translarna’s benefit-risk balance is negative and therefore recommended not renewing the marketing authorisation in the EU. EMA will now send the CHMP opinion to the European Commission, which will issue a final legally binding decision applicable in all EU Member States. 

[An example of risk management in practice involving early access to a medicine meant to address an unmet medical need. MBH] 

EMA recommends non-renewal of authorisation of multiple myeloma medicine Blenrep 

EMA’s CHMP has recommended not renewing the conditional marketing authorisation for Blenrep (belantamab mafodotin), a medicine used to treat multiple myeloma (a cancer of the bone marrow).This recommendation follows a review of available data by the CHMP as part of the renewal of Blenrep’s marketing authorisation In its review, the CHMP considered that results from a new study (DREAMM-3) did not confirm the effectiveness of Blenrep as agreed when conditional marketing authorisation was granted.  

However, on 21 September, the company that markets Blenrep asked for re-examination of the CHMP opinion. Upon receipt of the grounds of the request, the CHMP will re-examine its recommendation and issue a final recommendation. Once this re-examination is finalised EMA will send the CHMP final opinion to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.  

 

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.







Kommentare


bottom of page