Review of Developments in GMP and the Regulation of Medicines December 2023
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, Australian and PIC/s regulatory authorities. The topics covered in this edition of the “Update” include:
UK
The Medicines and Healthcare products Regulatory Agency (MHRA)
Innovative new medicine approvals (see product section)
Common issues identified during clinical trial applications
International Recognition Procedure additional guidance
Online Eligibility Checker tool for applications via the International Recognition Procedure (IRP)
Specific batches of carbomer-containing lubricating eye gels branded Aacarb, Aacomer and Puroptics recalled as a precaution due to possible microbial contamination
Health organisations to prepare now for new measures to reduce ongoing serious harms of valproate
EU
Concept paper on the development of an addendum to the Guideline on clinical development of vaccines on clinical trials for vaccines for immunocompromised individuals
First electronic product information (ePIs) published for selected human medicines
Q&A on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - Scientific guideline
VICH GL60 GMP for active ingredients used in veterinary medicinal products - Scientific guideline
Consumption of antimicrobials in animals reaches lowest level ever in Europe
Guidance on GMP & GDP: updated Q&A
Biosimilars in the EU
SME Office Newsletter
Reference standards
Updated version of the EuroGTP II tool to ensure good tissue and cell practices for human application
Virtual training programme: Ph. Eur. Texts related to biologicals and microbiology chapters
12th meeting of the European Network of Official Cosmetics Control Laboratories (OCCLs)
Falsification of medical devices – Results of European survey
USA
President Biden announces new actions to strengthen America’s supply chains, lower costs for families, and secure key sectors
Translation of GLP Study Reports: Q&A-Draft Guidance for Industry
International
Australia
Therapeutic Goods Administration (TGA)
Extension to oral cefalexin substitution instrument
Safety alert: potential contamination of some saline products with Ralstonia pickettii
Pharmaceutical Inspection Co-operation Scheme PIC/S
China applies for PIC/S membership
Egypt applies for PIC/S pre-accession
Products
MHRA authorises Litfulo as a treatment for severe alopecia
MHRA authorises Krazati as a treatment for non-small cell lung cancer in adults
MHRA authorises enzyme inhibitor Anastrozole to prevent breast cancer in post-menopausal women
MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia
MHRA Cystic fibrosis drugs Kaftrio and Kalydeco licensed for patients aged two to five years old
Precautionary action taken to amend incorrect expiry dates of flu nasal spray vaccines
Documents
Next-generation sequencing for adventitious virus detection in biologics
Fingerprint study on tadalafil API samples
Spikevax and Comirnaty COVID-19 Vaccines - EMA response to call for suspension.
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
Medicines and Healthcare products Regulatory Agency (MHRA)
Common issues identified during clinical trial applications
This guidance identifies common issues with validation and assessment of clinical trial applications and how to avoid them. More than half of all 950 – 1000 clinical trial authorisation (CTA) applications require additional information to be submitted before they are considered approvable. Many of the requests for further information or ‘grounds for non-acceptance’, are common and are avoidable if available guidance is followed or if a satisfactory justification for not following the applicable guidance is provided in the application.
International Recognition Procedure additional guidance
As of 6 Nov 2023, additional guidance has been added to address common queries about the International Recognition Procedures.
Online Eligibility Checker tool for applications via the International Recognition Procedure (IRP)
From 20 November 2023, applicants should use this new tool to determine whether their Marketing Authorisation Application (MAA) is suitable for IRP and to identify which route (A or B) to follow, before submitting an IRP application. The new IRP itself becomes operational in six weeks’ time, on 1 January 2024.The IRP is a further initiative to help bring life-saving medicines to UK patients that has been developed by the MHRA following the UK’s departure from the European Union. It allows the Agency to take into account the expertise of trusted regulatory partners in other countries when authorising medicines.
Specific batches of carbomer-containing lubricating eye gels branded Aacarb, Aacomer and Puroptics recalled as a precaution due to possible microbial contamination
The MHRA has issued precautionary safety advice regarding possible contamination of certain eye gels and has told patients and users of the affected products to stop using them immediately. They should return their product to the place of purchase.
These types of products are generally used to relieve the symptoms of dry eye. Those branded Aacarb, Aacomer and Puroptics, have a potential risk of microbial contamination, which can cause an infection if the gel is used.
Investigations are ongoing to determine if there is a link between the infections which have been identified and these products.
These eye gels are medical devices. The manufacturer (Indiana Ophthalmics LLP) has issued a Field safety Notice (FSN) to advise all customers of the required actions.
MHRA instructs health organisations to prepare now for new measures to reduce ongoing serious harms of valproate
Healthcare organisations are being instructed by the MHRA now to put in place a plan to implement the first phase of new regulatory measures to reduce the known harms of valproate, including the significant risk of serious harm to the baby if taken during pregnancy and the risk of impaired fertility in males.
From January 2024, valproate must not be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or unless there are compelling reasons that the reproductive risks do not apply. For the majority of patients, other effective treatment options are available.
All women who could become pregnant and girls who are currently taking valproate will be reviewed at their next annual specialist review, using a revised valproate Annual Risk Acknowledgement Form, which will include the need for a second opinion’s signature if the patient is to continue with valproate.
A similar system will be introduced later in 2024 for male patients currently taking valproate.
Europe
European Medicines Agency (EMA)
Concept paper on the development of an addendum to the Guideline on clinical development of vaccines on clinical trials for vaccines for immunocompromised individuals
Immunocompromised individuals are commonly excluded from the clinical trials conducted before the first licensure of new vaccines to avoid confounding of the immunogenicity and efficacy data. Therefore, it is common that there are no, or very limited data available from immunocompromised individuals when vaccines are first marketed. There is a need to supplement the Guideline on clinical evaluation of vaccines to address vaccine clinical development programmes in immuno-compromised individuals. The Vaccine Working Party and the Emergency Task Force recommend the development of an Addendum to the Guideline to address the issues identified above. The Addendum would provide guidance on appropriate clinical studies to be conducted in immunocompromised individuals before or after initial marketing authorization to evaluate the need for alternative dose regimens and to support inclusion of specific recommendations for use of vaccines in this population or in specific sub-populations in the Product Information.
The consultation period ends 30 Jan 2024.
First electronic product information (ePIs) published for selected human medicines
The Heads of Medicines Agencies (HMA), the European Commission (EC) and EMA have published for the first time electronic product information (ePI) for selected human medicines harmonised across the EU. The creation and testing of ePIs in real regulatory procedures is being explored through a one-year pilot initiative to enable the transition to the electronic system for medicines evaluated both nationally and at European level. The ePI initiative is an action under the Pharmaceutical Strategy for Europe supported by the EU funding programme,
The published ePIs are for medicines evaluated by EMA or by national authorities in Denmark, the Netherlands, Spain and Sweden. Companies participating in the pilot create and submit the ePI as part of their regulatory application. The pilot, which involves 25 medicines, will conclude in July 2024, and the outcomes will inform how to integrate the ePIs into common practice and expand their use across the EU. These ePIs were created following the EU ePI Common Standard to provide a consistent structure throughout all Member States and ensure the information works across different e-health platforms.
[Hopefully this will be a real step forward, though, no doubt there will be lots of obstacles to overcome MBH]
Q&A on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - Scientific guideline
This document outlines expected multidisciplinary (including quality, non-clinical, clinical) aspects of oral pressurised metered dose inhalers (pMDIs) intended for delivery of the active substance into the lungs for the treatment of conditions affecting the lungs and airways (such as asthma and COPD). In particular, the document aims at providing advice regarding data requirements for the replacement of hydrofluorocarbons (HFCs) used as excipients (propellants) in oral pressurised metered dose inhalers with low global warning potential propellants (LGWP).
VICH GL60 GMP for active ingredients used in veterinary medicinal products - Scientific guideline
This document provides guidance on GMP for the manufacturing of APIs used in veterinary medicinal products. It provides an appropriate system for managing quality and, as such, is intended to help ensure that APIs meet quality and purity standards. It applies to APIs manufactured by chemical synthesis, extraction, cell culture/fermentation, by recovery from natural sources, or by any combination of these.
Consumption of antimicrobials in animals reaches lowest level ever in Europe
European countries have substantially reduced sales of veterinary antibiotics, which translates into a lower risk of bacteria becoming resistant in people and animals.
Overall sales of veterinary antibiotics decreased by 53% between 2011 and 2022, reaching the lowest level ever reported, according to data from 25 countries.
During the same period, sales of antibiotic classes that are considered critically important in human medicine for veterinary use noticeably decreased: sales of third- and fourth- generation cephalosporins dropped by 49%, polymyxins by 81%, fluoroquinolones by 25% and sales of other quinolones dropped by 90%.
Guidance on GMP & GDP: updated Q&A
[EMA has published this updated Q&A. The most recent changes appear to be from January & July 2023 MBH]
These cover
Remote batch certification / confirmation by the QP
Residency of the QP
GDP requirements
Biosimilars in the EU
This document has been prepared jointly by the EMA and the European Commission.
The EU has pioneered the regulation of biosimilar medicines by establishing a solid framework for their approval and by shaping biosimilar development globally.
Since the EU approved the first biosimilar in 2006, healthcare professionals have gained increasing experience with their use. Today, biosimilars are an integral part of the effective biological therapies available in the EU, supported by adequate safeguards protecting patient safety.
A biosimilar is not regarded as a generic of a biological medicine. This is mostly because the natural variability and more complex manufacturing of biological medicines do not allow an exact replication of the molecular microheterogeneity. Consequently, more studies are needed for regulatory approval of biosimilars than for generics to ensure that minor differences do not affect safety
or efficacy.
SME Office Newsletter
Issue#60 of this quarterly newsletter for small & medium enterprises has now been published.
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Reference standards
3 new Ph. Eur. reference standards and 21 replacement batches released in October 2023. [Within this listing, readers should also take note of the Information on reference standards removed from catalogue. MBH]
Updated version of the EuroGTP II tool to ensure good tissue and cell practices for human application
To help ensure quality and safety in the field of substances of human origin (SoHO), the EDQM has been entrusted with managing the EuroGTP II tool for good tissue and cell practices.
Starting on 15 November 2023, this interactive assessment tool will be hosted on the EDQM SoHO platform, along with the Microbiological Risk of Contamination Assessment (MiRCA) tool
Identifying, quantifying and assessing the level of risk associated with novel SoHO preparations using a standard process is of crucial importance. Any modification in processes associated with the donation, procurement, testing, processing, storage and distribution of such preparations may impact the quality and/or safety of SoHO-related therapies and products and therefore pose a risk for donors or recipients.
Virtual training programme: Ph. Eur. Texts related to biologicals and microbiology chapters
EDQM has opened registration for its 2024 virtual training programme, composed of four independent modules on Ph. Eur. texts related to biologicals and on microbiology chapters. This is a great opportunity to learn about Ph. Eur. texts on biologicals, the implementation of pharmacopeial procedures and comparability of alternative procedures, and on microbiology testing, including for bacterial endotoxins. In addition, participants can get a deeper understanding of how texts are developed to offer the flexibility necessary to address complex biological products, discover more about the Ph. Eur. pyrogenicity strategy, aimed at phasing out the rabbit pyrogen test by 2025, and get an overview of the role and correct use of Ph. Eur. reference standards and of their establishment process.
12th meeting of the European Network of Official Cosmetics Control Laboratories (OCCLs)
The Swedish Medical Products Agency (MPA) hosted the meeting.
Observations and results from testing samples of teeth whitening products and skin bleaching products were shared.
Concerns were raised about nail varnishes contaminated with carcinogenic nitrosamines, as well as regarding the poor quality of cosmetics designed to appeal to children. To improve the safety of these products, co-ordinated pan-European product testing initiatives were launched.
Lastly, it was agreed that efforts to test tattoo inks and permanent make-up in Europe and to overcome the related analytical challenges should be stepped up.
Falsification of medical devices – Results of European survey
The falsification of medical devices is a serious international matter of concern, but little data is available, making it difficult to assess the current state of affairs.
The survey responses firstly confirmed the existence of the issue of falsified medical devices. However, few investigations (at criminal level, in particular) are instigated, and even fewer prosecutions. Data collection is practically inexistent, and hence very little data is available. To date, exchanges of information on this topic have been rare.
Medical devices – products or equipment intended for a medical purpose – form a vast category, comprising over 500,000 products available. The field is currently seeing major developments in terms of new technologies and new types of products.
United States of America
White House Briefing Room
President Biden announces new actions to strengthen America’s supply chains, lower costs for families, and secure key sectors
During the inaugural convening of the new White House Council on Supply Chain Resilience, President Biden will unveil more than 30 new actions to strengthen America’s supply chains.
[Readers should particularly note the section relating to Use of the Defense Production Act to make more essential medicines in America and to mitigate drug shortages. – MBH],
President Biden will issue a Presidential Determination to broaden the Department of Health and Human Services’ (HHS) authorities under Title III of the Defense Production Act (DPA) to enable investment in domestic manufacturing of essential medicines, medical countermeasures, and critical inputs that have been deemed by the President as essential to the national defense. HHS has identified $35 million for investments in domestic production of key starting materials for sterile injectable medicines. HHS will also designate a new Supply Chain Resilience and Shortage Coordinator for efforts to strengthen the resilience of medical product and critical food supply chains, and to address related shortages. HHS intends to institutionalize this coordination to advance the department’s supply chain resilience and shortage mitigation goals over the long term. The Department of Defense (DOD) will also soon release a new report on pharmaceutical supply chain resilience aimed at reducing reliance on high-risk foreign suppliers. These actions are a subset of the Administration’s broader work to increase access to essential medicines and medical products.
The US Food and Drug Administration (USFDA)
Translation of GLP Study Reports: Q&A-Draft Guidance for Industry
This guidance provides information to sponsors and nonclinical laboratories regarding the language translation of study reports for studies conducted in compliance with good laboratory practice (GLP) regulations (21 CFR part 58).2,3 GLP studies include, but are not limited to nonclinical toxicology studies, safety pharmacology studies, and device safety studies received by different FDA Centers. When study reports of GLP studies are translated from their original language into English, adequate documentation is critical to ensure accurate and complete study data are submitted to FDA. This Q&A document is intended to clarify FDA’s recommendations concerning the translation of study reports from a non-English language into English for studies conducted in compliance with GLP regulations. FDA expect that the recommendations for translating GLP study reports described in this guidance will increase FDA stakeholders’ understanding of the documentation needed to ensure study reports translated from the original language into English are clear, accurate, complete, and truthful.
This draft guidance does not address the reliable translation of other study reports submitted to support a marketing authorization, including studies that are not conducted in compliance with GLP regulations, but the concepts described in the guidance may be informative for the translation of study reports from those studies that are intended for submission to FDA to support a marketing authorization. [Readers should take particular note of this final paragraph as potentially useful outside the restrictions of the USA meaning of GLP MBH].
International
Australia
Therapeutic Goods Administration (TGA)
Extension to oral cefalexin substitution instrument
Due to the ongoing shortage of multiple strengths and presentations of oral cefalexin medicines TGA have extended the current Serious Scarcity Substitution Instruments (SSSI) which was due to expire on 31 October 2023 and now will remain in force until 30 April 2024 and continues to assist with timely access for patients using oral cefalexin syrups and suspensions.
Safety alert: potential contamination of some saline products with Ralstonia pickettii
TGA are aware of Ralstonia pickettii cases in patients across multiple states and territories and are working closely with state and territory health departments to investigate the possible role of therapeutic goods.
R. pickettii is a bacteria commonly found in the natural environment. It rarely causes infection in humans but may cause infection in people with weakened immune systems.
On 24 November 2023, TGA took the precautionary measure of initiating a nationwide quarantine for some Interpharma saline products to minimise possible risk to patients. This decision was made after the investigation identified that some batches of these products were likely to have been used in a cluster of patients who tested positive for R. pickettii.
As at 28 November 2023, the quarantine affects 3 products on the Australian Register of Therapeutic Goods (ARTG).
Pharmaceutical Inspection Co-operation Scheme PIC/S
China applies for PIC/S membership
China’s National Medical Products Administration (NMPA) submitted a membership application to PIC/S, following the successful completion and closure of the PIC/S pre-accession process.
NMPA will be the representative of all Chinese Authorities involved in the Chinese Good Manufacturing Practice Regulatory Compliance Programmes (GMPRCP) as defined by PIC/S.
The Committee appointed Jacques Morénas (France / ANSM) as Rapporteur, who will lead the PIC/S Audit Team which will manage and oversee NMPA’s accession process to PIC/S
Egypt applies for PIC/S pre-accession
The Rapporteur will be appointed by written procedure.
Products
MHRA authorises Litfulo as a treatment for severe alopecia
MHRA has authorised a new medicine called Litfulo (ritlecitinib), an enzyme inhibitor treatment for severe alopecia areata in patients 12 years and older. Litfulo is a hard capsule medicine, recommended to be taken in one 50mg dose a day by mouth.
Alopecia areata is a disease where the body’s own immune system attacks hair follicles, causing inflammation that leads to hair loss on the scalp, face and/or other parts of the body.
The active ingredient in this treatment, ritlecitinib, is an enzyme inhibitor. It works by reducing the activity of enzymes in the body called JAK3 and TEC kinases, which are involved in inflammation at the hair follicle. This reduces the inflammation, leading to hair regrowth in patients with alopecia areata.
MHRA authorises Krazati as a treatment for non-small cell lung cancer in adults
Krazati (adagrasib), is a treatment for a type of non-small cell lung cancer (NSCLC) in adults that has a mutation and produces a rare protein called KRAS G12C. It can be used to treat patients with this type of NSCLC when the disease is advanced or has spread to other parts of the body, and previous treatments have failed to stop the cancer’s growth.
Krazati is available in 200mg tablet form, with the recommended dose of three tablets taken at the same times twice a day.
The Marketing Authorisation was granted on 3 November 2023 to Mirati Therapeutics B.V.
MHRA authorises enzyme inhibitor Anastrozole to prevent breast cancer in post-menopausal women
Anastrozole is now authorised as a preventative treatment for post-menopausal women at moderate or high risk of breast cancer. Anastrozole was already authorised for use in the treatment of breast cancer in post-menopausal women and has been used off-label for prevention.
The treatment is taken as a 1mg tablet, once a day for 5 years.
Anastrozole is an aromatase inhibitor. This works by cutting down the amount of the hormone oestrogen that a patient’s body makes by blocking an enzyme called ‘aromatase’.
MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia
A new treatment for sickle-cell disease and transfusion-dependent β-thalassemia has been authorised by the UK MHRA for patients aged 12 and over after a rigorous assessment of its safety, quality and effectiveness.
Casgevy is the first medicine to be licensed that uses the innovative gene-editing tool CRISPR, for which its inventors were awarded the Nobel Prize in 2020.
MHRA Cystic fibrosis drugs Kaftrio and Kalydeco licensed for patients aged two to five years old
MHRA has extended the licence of the cystic fibrosis medicines Kaftrio (ivacaftor, tezacaftor and elexacaftor) and Kalydeco (ivacaftor) for children aged two to five years old.
These medicines were already authorised for use in treating cystic fibrosis with a common gene mutation in patients aged six years and older, and this announcement extends that authorisation.
Precautionary action taken to amend incorrect expiry dates of flu nasal spray vaccines
AstraZeneca UK has informed the MHRA that the printed expiry date for a limited number of batches of Fluenz Tetra nasal spray vaccines is incorrect.
Following routine testing, AstraZeneca observed that certain batches of Fluenz nasal spray vaccines dropped in potency faster than predicted once thawed. The manufacturer has since revised the expiry dates for all affected batches as a precautionary measure. These batches are safe to use and fully effective within the amended expiry date.
[An interesting and somewhat unusual situation. – Perhaps a good example of Risk Based decision making between the company and the MHRA. MBH]
Documents
Next-generation sequencing (NGS) for adventitious virus detection in biologics
The European Directorate for the Quality of Medicines & HealthCare (EDQM) has co-authored a report with a broad range of academics and interested parties.
The article, published in ‘Biologicals’, reports on an International Alliance for Biological Standardization (IABS) conference held in September 2022 that underlined the significant progress made in next-generation sequencing (NGS, also called high-throughput sequencing, or HTS) in a context where the limitations of current testing methods for adventitious virus detection in biologics have become apparent. NGS, a powerful technology for broad virus detection, was further developed after it was found that, in certain cases, conventional techniques failed to detect novel or even known viruses. The complexity of NGS and its use nevertheless create challenges in regulation, standardisation, validation and bioinformatics, including in terms of data analysis, storage and follow-up strategies to confirm results.
The conference report provides details of the presentations and discussions that took place during the event, including:
the latest advances in NGS and their impact on biological product control;
the regulatory and health authority perspectives on using NGS for adventitious virus testing;
reference materials, NGS qualification and validation;
NGS applications for adventitious virus testing;
strategies for optimisation of NGS virus detection and follow-up of NGS signals ;
expectations for NGS implementation.
Fingerprint study on tadalafil API samples
The Active Pharmaceutical Ingredient (API) Working Group of the General European OMCL Network (GEON) has conducted a market surveillance study on tadalafil, the results of which have been published in the Journal of Pharmaceutical Sciences Vol. 112 (2023).
An API fingerprint is a specific analytical profile that includes information on the physico-chemical properties of the substance. API fingerprint studies are performed in order to identify substandard or falsified APIs, which might represent a threat to patient health.
In the study, OMCLs tested the pharmaceutical quality of samples, checked compliance with the monograph of the Ph.Eur and used chemometric methods to establish analytical fingerprints. These fingerprints may then be used to differentiate between manufacturing sources in future authenticity investigations.
Spikevax and Comirnaty COVID-19 Vaccines EMA response to call for suspension.
EMA has published this response to questions arising from a group of eight Honourable Members of the The European Parliament.
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.
