Review of Developments in GMP and the Regulation of Medicines May 2024
During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry.
The topics covered in this edition of the “Update” have come from the UK, EU, USA and Australian regulatory authorities.
UK MHRA
Applying for a parallel import licence
Modified MAGEC X system for early onset scoliosis treatment
Medicines that you cannot export from the UK or hoard
Precautionary recall of some sodium chloride solutions for irrigation, eyewash and inhalation.
EU
GMP? /GDP Guidance Q&A
Post-authorisation procedural advice for users of the centralised procedure
New recommendations to strengthen supply chains of critical medicines
European Shortages Monitoring
Cancer Medicines Forum: February 2024
Real-world evidence provided by EMA
Pharmaceutical quality of inhalation and nasal medicinal products
Requirements for demonstrating therapeutic equivalence between orally inhaled products for asthma and chronic obstructive pulmonary disease
Confidentiality arrangement between the EU and the Republic of Korea
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Critical medicine shortages - immediate workflow and trial phase with two ongoing shortages
Shortage of aprepitant, powder for oral suspension – Expert opinion of the EDSForm Working Party
Public consultation on Traceability of Medicines in Hospital Settings
New general chapter on Phage therapy medicinal products (5.31) adopted and pre-published on the EDQM website
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies
Pharmeuropa 36.2 just released
Revised EDQM guideline “content of the dossier” and other key documents.
JP and Ph. Eur. launch a bilateral prospective harmonisation project for active substance and medicinal product monographs
How to identify the manufacturing sites linked to CEP application (revised)
reference standards
Cannabidiol impurity J CRS available
Ireland HPRA
Guide to attainment of QP status in Ireland
USA
Data Integrity for In Vivo Bioavailability and Bioequivalence Studies
Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products Q&A Guidance for Industry
Content and Format of Composition Statement and Corresponding Statement of Ingredients in Labeling in NDAs and ANDAs
International
Australia
Therapeutic Goods Administration
All medicinal cannabis products supplied to Australian patients must meet quality standards
Products
Combined antibiotic approved to treat adult patients with severe infections of the urinary tract and hospital-acquired pneumonia
COVID-19 vaccine strain updates: Global regulators agree on timing and data requirements
EMA’s ETF recommends updating COVID-19 vaccines to target new JN.1 variant
Conferences
EMA multi-stakeholder workshop on psychedelics – Towards an EU regulatory framework
Information and Q&A session on updated CAPs in web-based eAF
Industry Update webinar on Regulatory Procedure Management for Product Lifecycle Management on IRIS
EMA workshop on the challenges in drug development, regulation and clinical practice in hemoglobinopathies
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Applying for a parallel import licence (updated)
This guidance explains how to get a parallel import licence for your medicine in the UK, including pharmacovigilance requirements and submitting your application.
It was last updated 8 April 2024 to reflect guidance on UK Parallel Import Licences Following Agreement of the Windsor Framework.
Modified MAGEC X system for early onset scoliosis treatment can now be used in the UK
Following an extensive assessment by the MHRA, as of 23 February 2024, the UK suspension of the MAGnetic Expansion Control (MAGEC) System (modified MAGEC X system only) has been lifted.
The MHRA is satisfied that the manufacturer, NuVasive Specialized Orthopedics (NSO), has put in place sufficient measures to provide reassurance about the safety of this device.
The modified MAGEC X system can now be appropriately selected for use in surgery for early onset scoliosis treatment in accordance with the manufacturer’s instructions for use. All previous generations of the MAGEC system (MAGEC 1,1.5, 2B) remain suspended in the UK and should not be implanted.
The MHRA will continue to monitor the safety and performance of the MAGEC system.
Medicines that you cannot export from the UK or hoard
On 24 April 2024 Vinblastine (strength: 10mg/10ml, pharmaceutical form: solution for injection vials) and Aztreonam (strength: all, pharmaceutical form: powder for solution for injection vials) were added to the list:
Precautionary recall of some sodium chloride solutions for irrigation, eyewash and inhalation.
Batches of some products made by Legency Remedies Pvt Ltd have been found to contain a bacteria called Ralstonia pickettii (R. pickettii). All potentially affected batches are being recalled following an MHRA investigation.
The UK Health Security Agency (UKHSA) is investigating a cluster of R. pickettii cases. There have also been similar cases reported in Australia.
Analysis of the UK and Australian R. pickettii samples from affected cases show that they are very closely related which suggests they share a common source. The Australian cases were linked to contaminated saline products utilised for irrigation and eyewash purposes in healthcare and care facilities.
Europe
European Medicines Agency (EMA)
GMP? /GDP Guidance Q&A
Updated document published 26.04 24
Post-authorisation procedural advice for users of the centralised procedure
The following sections of this Q&A document have been updated as of March 2024
1 Type IA Variations - Q1.3
4. Extension of marketing authorisation – Q4.12
13. Post Authorisation Safety Study (PASS) – Q13,2
19. Transfer of Marketing Authorisation – Qs 19.1 19.2 19.5, 19,8, 19.13-15
New recommendations to strengthen supply chains of critical medicines
EMA has published a number of recommendations to address vulnerabilities in the production and delivery of medicines included in the Union list of critical medicines and strengthen their supply chain. These recommendations have been developed by EMA’s Medicines Shortages Steering Group (MSSG) and will facilitate the availability and supply of critical human medicines for which vulnerabilities in the supply chain have been identified.
Measures considered by the MSSG will be selected according to the risks posed to the supply chain and the type of medicine. The MSSG will work closely with the European Commission’s Critical Medicines Alliance (CMA). The MSSG will develop regulatory and governmental policy recommendations focused on short- to medium-term actions, while the CMA will focus on long-term measures in the field of industrial policy to address vulnerabilities in the supply chain of critical medicines.
European Shortages Monitoring Platform
EMA is setting up the European Shortages Monitoring Platform (ESMP) to gather information about medicine supply and demand in order to prevent, detect, and manage human medicine shortages in the European Union (EU) and European Economic Area (EEA).
EMA will collect data via the platform from the national competent authorities (NCAs) and marketing authorisation holders (MAH).
The first version of the platform will be available by February 2025.
The European Shortages Monitoring Platform will enable EMA to monitor the supply, demand and availability of critical medicines needed during crisis situations, which can be public health emergencies or major events.
Outside of crises, EMA will use the platform in two ways:
to monitor supply and availability of medicines when asked
for preparedness activities to prevent and manage shortages which might lead to a public health emergency or major event
Cancer Medicines Forum: February 2024
The Cancer Medicines Forum (CMF) aims to explore how EMA can contribute towards addressing remaining uncertainties about the use of cancer medicines in clinical practice.
The forum brings together representatives of academic organisations from EMA’s Healthcare Professionals Working Party and the European medicines regulatory network.
The results of discussions will support the prioritisation of actions to fight cancer in EMA's Regulatory Science Strategy to 2025 and Academia Collaboration Matrix Action Plan.
The meetings of the forum are by invitation only.
[Interested readers should also access the “pragmatic clinical trials” and “factors affecting the feasibility of post-authorization RCTs for conditionally authorized anticancer medicines” presentations plus the minutes from the February meeting.
Real-world evidence provided by EMA
The use of Real-World Data (RWD) is increasingly embedded in the scientific evaluation of human medicines. EMA has direct and indirect access to RWD in the form of patient electronic medical records which can be used to facilitate regulatory evaluations and inform decision-making. On this basis, EMA provides a service to generate and deliver Real-World Evidence (RWE) to EMA’s scientific committees, national competent authorities (NCAs), EMA functions and other EU decision-makers and partner organisations.
This document briefly describes how RWE, derived from the analysis of RWD, can be useful in the context of regulatory decision-making, the types of studies that can be performed and how EMA can help identify the best resources to address a research question. The process for requesting RWD studies is also explained.
All work on RWD is conducted in full compliance with data protection legislation.
Revised Guideline on the pharmaceutical quality of inhalation and nasal medicinal products
This is the first revision of the guideline on pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005 Corr). The main aim of the first revision is to consolidate the information available in the previous guidance documents, the related published Q&A, also taking into consideration recent advancements in the field, common practice and new regulations, including the medical device regulation. Requirements for demonstration of therapeutic equivalence for orally inhaled products (OIP) are included in the Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD). These two guidelines are complementary and should be read in conjunction to each other.
Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)
This guideline is the 2nd revision of the CHMP Guideline formerly called “Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and COPD in adults and for use in the treatment of asthma in children and adolescents”. It addresses the requirements for demonstration of therapeutic equivalence (TE) between orally inhaled products containing the same active moiety(ies).
Confidentiality arrangement between the EU and the Republic of Korea
EMA and the European Commission’s Directorate-General for Health and Food Safety (DG SANTE) have signed a working arrangement with the Ministry of Food and Drug Safety (MFDS) of the Republic of Korea for the exchange of confidential information on medical and medicinal products.
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Critical medicine shortages - immediate workflow and trial phase with two ongoing shortages
The task of the European Drug Shortages Formulary Working Party (EDSForm WP), created at the end of November 2023, is to define both short-term and long-term actions aimed at mitigating the negative impact of medicine shortages on public health.
Short-term actions involve compiling technical recommendations on the preparation of unlicensed pharmaceutical preparations that could be used during ongoing shortages of licensed medicinal products.
Long-term actions consist in the prospective elaboration of monographs describing standardised unlicensed preparations that can be used as a temporary replacement for the licensed product during a shortage, and their subsequent compilation in the European Drug Shortages Formulary.
To this end, at its 178th Session (19-20 March 2024), the European Pharmacopoeia Commission (EPC) approved a dedicated “immediate” workflow proposed by the new EDSForm WP that will allow the experts of the WP to produce – rapidly – technical recommendations in response to an ongoing shortage.
The EPC decided to use two ongoing critical medicine shortages (paediatric forms of aprepitant and amoxicillin) to trial and refine this immediate workflow.
[See the item below for a summary of the first such “expert opinion” MBH]
Shortage of aprepitant, powder for oral suspension – Expert opinion of the EDSForm Working Party
The European Drug Shortages Formulary (EDSForm) Working Party has compiled existing knowledge on extemporaneous oral liquid formulations of aprepitant that have been or are being used to alleviate the lack of age-appropriate licensed products. The information and recommendations provided in the resulting first expert opinion are intended to help healthcare professionals in their risk assessment and decision-making processes when faced with the temporary unavailability of Emend 125 mg powder for oral suspension in the setting described above.
The EDQM and the EDSForm Working Party remind users that, wherever possible, it remains preferable to use a licensed medicine rather than an unlicensed pharmaceutical preparation and that it is the responsibility of the healthcare professionals involved to carry out the risk analysis for each patient.
Public consultation on Traceability of Medicines in Hospital Settings
EDQM is seeking comments from interested parties on a draft guidance document on the topic of “Traceability of Medicines in Hospital Settings”.
The objective of this project is to provide regulatory authorities and stakeholders with a guidance document on the minimum requirements to be fulfilled for full in-hospital traceability of medicines, from their arrival on-site until their administration to patients.
To facilitate the processing of responses from a wide range of interested parties, we can only accept comments submitted by national competent authorities and European or national associations, organisations or bodies.
The closing date for this survey and the public consultation is 3 May 2024
New general chapter on Phage therapy medicinal products (5.31) adopted and pre-published on the EDQM website
Rising levels of antimicrobial resistance in recent years, identified as one of the leading threats to global public health and development, have prompted renewed interest in the use of phage therapy for the treatment of bacterial infections. This led the European Pharmacopoeia Commission (EPC) to make the elaboration of Ph. Eur. texts standardising requirements for phage therapy one of its top priorities.
Phage therapy medicinal products (5.31), the first such text, was adopted by the EPC at its 178th session March 2024. This new general chapter provides a framework of requirements for the production and control of phage therapy products and allows a degree of flexibility commensurate with the complex approaches currently employed in this emerging and rapidly developing field.
Phage therapy medicinal products is the first up-to-date text of its kind to be published in a pharmacopoeia.
Survey on strategy for Ph. Eur. quality standards for monoclonal antibodies (mAb)
The European Pharmacopoeia Commission (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.
Pharmeuropa 36.2 just released
All new European Pharmacopoeia (Ph. Eur.) texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation.
Users and interested parties are welcome to comment on these drafts.
The deadline for comments on Pharmeuropa 36.2 is 30 June 2024.s.
Revised EDQM guideline “content of the dossier” and other key documents.
The revised version of this EDQM guideline is now available and will be implemented as of 1st May 2024. This guideline and other key documents (QOS, top ten deficiencies), as well as the use of EMA SPOR/OMS ORG_ID and LOC_ID are essential to avoid a CEP dossier being blocked at receipt or receiving requests for additional information.
Changes introduced in this revised guideline aimed to align requirements with the current regulatory environment (since the previous version of this document was implemented in January 2019). In particular, the guideline has been updated with regards to certain information to be included in the 3 modules of the submission
JP and Ph. Eur. launch a bilateral prospective harmonisation project for active substance and medicinal product monographs
The Japanese Pharmacopoeia (JP) and the European Pharmacopoeia (Ph. Eur.) are pleased to announce the launch of a bilateral prospective harmonisation project targeting pharmacopoeial standards for active substances and medicinal products.
Pharmacopeial harmonisation serves to further reduce the burden on manufacturers to perform different compendial tests by aligning the pharmacopoeial standards in different regulatory jurisdictions.
Macitentan and macitentan tablets have been selected as the first candidates for this co-operation.
How to identify the manufacturing sites linked to CEP application (revised document)
This guidance document has been updated to complete the identification of the manufacturing sites by the SPOR OMS coordinates. The use of these coordinates is mandatory, and companies should ensure that their organisation name and location address(es) given to the EDQM are in line with the data published in the SPOR/OMS database. EDQM will use the entries in the SPOR/OMS database as a reference in order to have consistent data.
Reference standards
7 new Ph. Eur. reference standards and 17 replacement batches were released in March 2024
Cannabidiol impurity J CRS now available
The standard cannabidiol impurity J CRS that is described in the monograph on Cannabidiol (3151) is now available for users under catalogue code Y0002436.
Ireland
The Health Products Regulatory Authority (HPRA)
Guide to attainment of QP status in Ireland
The legislation references in this document have been updated. Version 5 of the document and a changes tracked version are available.
United States of America
The US Food and Drug Administration (USFDA)
Data Integrity for In Vivo Bioavailability and Bioequivalence Studies
The purpose of this guidance is to provide recommendations to applicants and testing site management on achieving and maintaining data integrity for the clinical and bioanalytical portions of bioavailability (BA) and bioequivalence (BE) studies submitted in support of investigational new drug applications (INDs), new drug applications (NDAs), and abbreviated new drug applications (ANDAs), and the bioanalytical portion of clinical pharmacologic studies supporting CDER-regulated biologic license applications (BLAs) as well as amendments and supplements to these applications. In addition, the recommendations in this guidance apply to the bioanalytical portion of nonclinical studies. FDA also encourages applicants and testing sites to consider these recommendations when conducting other studies, including in vitro and pharmacology and toxicology studies.
FDA expects that all data submitted to the Agency, including data from BA and BE studies submitted in support of INDs, NDAs, and ANDAs and clinical pharmacologic studies submitted in support of BLAs, is accurate, complete, and reliable, and that industry maintain data integrity throughout the data lifecycle of the product(s) or biologic therapeutic(s).
For purposes of this guidance, data integrity refers to the accuracy, completeness, and reliability of data. Accurate, complete, and reliable data should be attributable to the person generating the data, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA). These characteristics of the data should be maintained throughout the data lifecycle. In recent years, FDA has observed data integrity concerns during the inspection of testing sites, clinical testing sites, and analytical testing sites, and during the assessment of the BA and BE study data submitted in support of applications. Data integrity concerns can impact application acceptance for filing, assessment, regulatory actions, and approval as well as post-approval actions, such as therapeutic equivalence ratings.
Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products Q&A Guidance for Industry
This revised draft guidance addresses questions firms may have when developing FDA-regulated promotional labeling and advertisements (promotional communications) for prescription reference products licensed under section 351(a) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(a)) and prescription biosimilar products, including interchangeable biosimilar products, licensed under section 351(k) of the PHS Act (42 U.S.C. 262(k)).
This guidance does not make any recommendations for nonprescription products. This guidance discusses considerations for presenting data and information about reference products or biosimilar products in these promotional communications to help ensure that they are accurate, truthful, and non-misleading.
Content and Format of Composition Statement and Corresponding Statement of Ingredients in Labeling in NDAs and ANDAs
This guidance is intended to assist new drug application (NDA) and abbreviated new drug application (ANDA) applicants in submitting an accurate and complete composition statement in their applications and corresponding statement of ingredients in the labeling, when applicable. This guidance describes best practices for writing the composition statement and corresponding statement of ingredients in labeling. This guidance recommends how applicants can provide complete information with the goal of minimizing the number of assessment cycles and communications that are necessary for approval, as well as ensuring product labels are written clearly.
International
Australia
All medicinal cannabis products supplied to Australian patients must meet quality standards
TGA is aware of recent media reports regarding questionable medicinal cannabis products being supplied in Australia.
The TGA would like to confirm that regardless of whether cannabis oil or cannabis flower medicine comes from overseas or Australia, it must comply with the relevant quality standard.
In Australia, the Therapeutic Goods Order 93 (TGO 93) is the relevant standard that sets out the testing, labelling and manufacturing requirements for medicinal cannabis products. Products that do not meet these requirements may not be safe or deliver the intended therapeutic effect.
Companies or individuals supplying products that do not meet TGO 93 requirements can be subject to fines or other penalties under the Therapeutic Goods Act 1989. These offence provisions apply to everyone in the supply chain, not just the importer or sponsor.
Products
Combined antibiotic approved to treat adult patients with severe infections of the urinary tract and hospital-acquired pneumonia
MHRA has approved the combined antibiotic cefepime/enmetazobactam (Exblifep 2 g/0.5 g powder for concentrate for solution for infusion) to treat adult patients with complicated infections of the urinary tract (bladder and kidneys) and certain types of pneumonia (infection of the lungs) that occur during a hospital stay. The combined antibiotic can also be used to treat bacteraemia (bacteria in the blood) due to, or possibly due to, any of the infections listed above.
Cefepime/enmetazobactam has been approved in 55 days through the MHRA’s new International Recognition Procedure (IRP), which supports expedited approvals for treatments in the UK market thanks to international recognition. The IRP allows the MHRA to accelerate the assessment of new medicines by considering the expertise and decision-making of trusted regulatory partners in the authorisation process.
COVID-19 vaccine strain updates: Global regulators agree on timing and data requirements
Currently authorised vaccines, particularly those that have already gone through adaptation of the composition, continue to be effective at preventing hospitalisation, severe disease and death due to COVID-19. However, protection wanes over time and as new SARS-CoV-2 variants emerge. For this reason, update of vaccine composition has to be considered on a regular basis. Meeting participants stressed that international convergence on the process and timing of COVID-19 vaccine strain updates are therefore critical in view of the continuous evolution of SARS-CoV-2. The meeting report provides an overview of key regulatory considerations related to updated COVID-19 vaccine composition. It also highlights data requirements for authorised vaccines to support the approval of strain changes. Workshop participants also discussed virus evolution and circulation in different regions of the world.
ETF recommends updating COVID-19 vaccines to target new JN.1 variant
EMA’s Emergency Task Force (ETF) has recommended updating COVID-19 vaccines to target the new SARS-CoV-2 variant JN.1 for the 2024/2025 vaccination campaign.
JN.1 differs from the XBB family targeted by previous updated vaccines and has now surpassed the XBB variants to become the most widely circulating variant worldwide.
The evidence indicates that targeting JN.1 will help maintain the effectiveness of the vaccines as SARS-CoV-2 continues to evolve.
Marketing authorisation holders should now contact EMA to discuss updates to the marketing authorisations of their vaccines. All marketing authorisation holders are expected to update the composition of their authorised vaccines in accordance with this recommendation.
Conferences
EMA multi-stakeholder workshop on psychedelics – Towards an EU regulatory framework
This multi-stakeholder workshop will bring together patients, healthcare professionals, academia, regulators, and industry to discuss the development and therapeutic use of psychedelic substances to address unmet medical needs in the area of mental health. The workshop will be broadcast live and the recording will be made available after the event.
Information and Q&A session on updated CAPs in web-based eAF
Tuesday, 07 May 2024, 10:00 (CEST) - 11:00 (CEST)Centrally Authorised Products (CAPs) data that is now available in the web-based electronic Application Form (eAF). EMA is hosting this information and Q&A session to explain and showcase the changes in the product data in the web-based Human Variations eAF. Participants will have the opportunity to ask questions in the last part of the session. Participation is recommended to industry stakeholders working on regulatory affairs of their respective organisations.
Industry Update webinar on Regulatory Procedure Management for Product Lifecycle Management on IRIS
The Regulatory Procedure Management (RPM) for Product Lifecycle Management (PLM) team is hosting a public webinar to offer Marketing Authorisation Holders an update on the progress of RPM plans, providing insights into the strategic direction, key milestones and implementation approach for the coming months. The webinar will also include a live demonstration of the Industry Portal, enabling participants to discover the new features and functionalities developed. The 1st transition of RPM for PLM to IRIS took place on 23 January 2024. In 2024, work is continuing with the development of further regulatory procedures in IRIS: Periodic Safety Update Reports, Post Authorisation Measures, Line extensions, Renewals, Annual Reassessments, Post-Authorisation Safety Study and Referrals. The aim is to manage the majority of procedures, except Initial Marketing Authorisation and other pre-submissions applications, exclusively in IRIS for all CAPs (and, consequently, for all MAHs with CAPs). In this regard, a 2nd roll-out will be performed in Q4 2024.
EMA workshop on the challenges in drug development, regulation and clinical practice in hemoglobinopathies
This workshop is organised in order to have a multi-stakeholder’s perspectives on sickle disease and thalassaemia before initiating the drafting of new guidelines for both diseases. This is in line with the haematology work plan for 2024.
The aims of the workshop are:
To present the epidemiology and disease background in adults and children with sickle cell and thalassemia, the current International treatment guidelines and the overview of the authorised medicines/treatments in the EU and in US for sickle cell and thalassemia.
To present the challenges in treatment/drug development from a clinicians’ perspective with regards to study design and endpoints used in clinical trials as well as the introduction of new therapies such as gene therapy (including gene editing products).
Registration is open until 27 June 2024.
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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