Review of Developments in GMP and the Regulation of Medicines August 2024
This month reported issues have come from the UK, EU, USA and WHO regulatory authorities.
The topics covered in this edition of the “Update” include:
UK MHRA
Man sentenced for illegally importing unlicensed medicines
New medicine approvals:- Ocrelizumab, capivasertib (Truqap), vibegron
EU
European Medicines Agency (EMA)
Slide-deck- European Shortages Monitoring Platform (ESMP) Essentials and Industry Reporting Requirements Webinar.
Update on the development of the European Shortages Monitoring Platform
Regulatory/HTA interface under the HTA Regulation (HTAR)
Revised CTIS transparency rules and new version of the public portal
International collaboration to facilitate medicines availability. - Global assessment / Inspection pathways
Guideline on the chemistry of active substances (Draft)
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Council of Europe adopts recommendation on reporting of disappearances of medicines
Publication of BSP study outcome on anti-D antibodies in IVIG reference standards available online
New monographs on an anti-interleukin monoclonal antibody
Ph. Eur. seeks feedback on the use of plastic additive 18.
Shortage of amoxicillin paediatric products: expert opinion of the European Drug Shortages Formulary Working Party
Ireland HPRA
New regulation on substances of human origin (SoHO)
USA
The US Food and Drug Administration (USFDA)
Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Q&A
Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products
Addressing misinformation about medical devices and prescription drugs Q&A
International
Australia
Therapeutic Goods Administration (TGA)
Australian Sunscreen Exposure Model
Business surrender scheme for vaping goods
Telehealth businesses fined over $300,000 for alleged unlawful advertising of weight loss medicines
PIC/S
Pharmaceutical Inspection Co-operation Scheme (PIC Scheme)
2024 PIC/S Seminar (Brasilia, Brazil)
Documents
USA FTC Releases Interim Staff Report on Prescription Drug Middlemen (PDM)
Products
Ocrelizumab approved as an injection to treat multiple sclerosis in adults
Capivasertib approved to treat patients with advanced breast cancer
Vibegron (Obgemsa) to treat the symptoms of overactive bladder syndrome in adults.
MHRA approves GLP –1 receptor agonist semaglutide to reduce risk of serious heart problems in obese or overweight adults
EMA confirms its recommendation to update the antigenic composition of authorised COVID-19 vaccines for 2024-2025
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
Medicines and Healthcare products Regulatory Agency (MHRA)
Man sentenced for illegally importing unlicensed medicines
A man who had unlicensed medicines sent to his parents’ address, has been sentenced at Southwark Crown Court to a 3 ½ year term of imprisonment, having earlier been found guilty of criminal activity in May. The sentencing follows an investigation by the MHRA’s Criminal Enforcement Unit (CEU) into the illegal supply of unlicensed medicines.
His activities came to the attention of the CEU following the interception of a series of parcels by UK Border Force officers during routine checks at airports and throughout the postal system.
New medicine approvals
See the Products section of this Regulatory Update for further details on recent MHRA approvals of:-
· Ocrelizumab approved as an injection to treat multiple sclerosis in adults
· capivasertib (Truqap) for patients with advanced hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer
· vibegron (Obgemsa) to treat the symptoms of overactive bladder (OAB) syndrome in adults
· the first generic raltegravir medicines to treat adult and paediatric HIV patients
· GLP –1 receptor agonist semaglutide to reduce risk of serious heart problems in obese or overweight adults
Europe
European Medicines Agency (EMA)
Slidedeck-European Shortages Monitoring Platform (ESMP) Essentials and Industry Reporting Requirements Webinar.
The slide-deck from this 24 June 2024 webinar includes sections on
· Shortage management in the EU,
· Overview of the European Shortages Monitoring Platform (ESMP),
· ESMP functionalities,
· Next steps,
· Q&A
Update on the development of the European
Shortages Monitoring Platform (ESMP)
This presentation arises from the Industry Stakeholder Group (ISG) 28 June 2024
Regulatory/HTA interface under the HTA Regulation (HTAR)
EMA and the European Network for Health Technology Assessment (EUnetHTA) have been working closely on topics of mutual interest Since 2010. Cooperation was facilitated through coordination of HTA bodies in EU-financed Joint Actions, and a subsequent tender for service (EUnetHTA) ceased to exist in mid-September 2023)
The EMA and the European Network for Health Technology Assessment (EUnetHTA) have been working closely on topics of mutual interest. Cooperation was facilitated through coordination of HTA bodies in EU-financed Joint Actions
The new HTA Regulation in Europe, becomes applicable from January 2025. The aim of this regulatory/HTA cooperation is to build synergies between regulatory evaluation and HTA along the medicine lifecycle
There are 3 key milestones along the implementation time-line
· 13 January 2025 for Medicinal products with new active substances for cancer treatment and also for Advanced Therapy Medicinal Products (ATMPs)
· 14 January 2028 for Orphan medicinal products
· 14 January 2030 for all other medicinal products under Article 7 of Regulation 2021/2282
With the dates referring to receipt of MAA submission by EMA
Revised CTIS transparency rules and new
version of the public portal
This presentation arises from the Joint PCWP – HCPWP meeting, of 2 July 2024.
The main differences with previous rules are:
· Publication focused on key documents of interest
· Documents are published earlier in time, due to the
· removal of deferral functionality
· Use of redaction as the method to protect Commercially Confidential Information (CCI)
· All trials’ applications submitted on or after 18 June 2024 follow the revised rules and all trials submitted before 18 June (‘historical’ trials) have their structured data published.
International collaboration to facilitate medicines availability. Global assessment / Inspection pathways
This presentation provides an update on the current ICMRA pilots.
14 applications were received; 5 cases were selected based on impact to supply and have been reviewed collaboratively They include new drug substance & drug product manufacturing sites, new QC testing sites, changes to the drug substance manufacturing process.
Included were 2 x small molecules, 2 x monoclonal antibodies (mAbs), 1 x Antibody-drug-conjugate (ADC)
The same submission was submitted to all Authorities The number of participating Reg Authorities was up to 4; number of Observers was also up to 4
The Pilot is still open for limited number of applications till transition to a new phase
Guideline on the chemistry of active substances (Draft)
This guideline replaces the ‘Note for guidance on chemistry of new active substances’ CPMP/QWP/130/96, Rev 1) and ‘Chemistry of active substances’(3AQ5a). It has been revised to cover new and existing active substances in one guideline.
The purpose of this guideline is to set out the type of information required for the manufacture and control of active substances (existing or new chemical entities) used in a medicinal product. The differences in requirements for new or existing active substances are clarified in the relevant paragraphs of the guideline where applicable.
This guideline is not applicable to herbal, biological, biotechnological products, radiopharmaceuticals and radiolabelled products. The guideline does not apply to contents of submissions during the clinical research stages of drug development. Nevertheless, the development principles presented in this guideline are important to consider during the investigational stages.
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Council of Europe adopts recommendation on reporting of disappearances of medicines
In the past decade, Europe has seen a number of major pan-European cases where medicines have disappeared from the legal supply chain, and then been manipulated or tampered with before being reintroduced into it. This clearly presents a risk for public health. Follow-up enquiries and discussions on a European level in the wake of these cases identified several gaps of concern. In particular, thefts are rarely reported to the health regulatory authorities in charge of the medicines supply chain and responsible for their safety and quality: theft being a criminal matter, if reported at all, these cases would be notified to the law-enforcement authorities, and sometimes only to the regional law-enforcement offices.
The Committee of Experts on Minimising Public Health Risks Posed by Falsification of Medical Products and Similar Crimes (CD-P-PH/CMED) has drafted a recommendation that aims to address these issues.
Recommendation CM/Rec (2024)3 of the Committee of Ministers to member States on reporting of disappearances of medicinal products for human and veterinary use from the legal supply chain was adopted by the Council of Europe Committee of Ministers on 10 April 2024.
Publication of BSP study outcome on anti-D antibodies in IVIG reference standards available online
A new article on the outcome of the study for the establishment of replacement batches of reference standards to control the level of anti-D antibodies in human immunoglobulin products for intravenous administration has been published in the online journal Pharmeuropa Bio & Scientific Notes.
The publication provides a detailed description of the method, materials and results of an international collaborative study (BSP131) during which the European Pharmacopoeia Immunoglobulin (anti-D antibodies test) Biological Reference Preparation (BRP) batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 were established. The study was conducted jointly by the USFDA, the National Institute for Biological Standards and Control (now the Medicines & Healthcare products Regulatory Agency, a World Health Organization collaborating centre) and the EDQM Biological Standardisation Programme (BSP), thus ensuring harmonised reference standards across the three institutions.
New monographs on an anti-interleukin monoclonal antibody
The European Pharmacopoeia (Ph. Eur.) has published two new draft monographs, Ustekinumab concentrated solution (3165) and Ustekinumab injection (3188), for public comment in this quarter’s issue of Pharmeuropa (36.3).
All interested parties are invited to review the drafts and submit comments on their technical content, via the appropriate channel. Stakeholder input will be key to refining and evolving the proposed monograph specifications, and to ensuring that they are and remain fit-for-purpose in a rapidly evolving multi-product market.
The commenting period runs until 30 September 2024.
Ph. Eur. seeks feedback on the use of plastic additive 18.
Plastic additive 18 is a phenolic antioxidant that may be used as a stabiliser in the processing of plastic materials. It consists of seven components, all of which contribute to the efficiency of the additive, but is a product-by-process (reaction product) rather than a physical mixture. It comprises one main component and what are essentially the isomers of that component. The members of European Pharmacopoeia (Ph. Eur.) Group 16 (the group responsible for texts on plastic materials and containers) are not certain if this additive – which is only mentioned in Ph. Eur. general chapters Polyolefins (3.1.3) and Plastic additives (3.1.13) – is still in use. In addition, from an analytical point of view, detection and quantification of the components of the additive is complex, especially in the presence of other plastic additives, and some of the components are prone to degradation (oxidation). This makes it difficult to establish reasonable quality criteria that can be measured with a standardised compendial method for products-by-process.in order to make an informed recommendation on the fate of plastic additive 18 in the Ph. Eur., the members of Group 16 are seeking your advice and assistance on this issue:
The Ph.Eur asks the question:-“To your knowledge, is plastic additive 18 still used in any plastic materials for containers for pharmaceutical use?”
Shortage of amoxicillin paediatric products: expert opinion of the European Drug Shortages Formulary Working Party
Amoxicillin is an aminopenicillin used to treat a number of infections. In recent years (particularly during the winter months), several member states have reported major difficulties in procuring amoxicillin-containing products, with paediatric forms of the antibiotic especially affected.
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.
Ireland
The Health Products Regulatory Authority (HPRA)
New regulation on substances of human origin (SoHO)
On 17th July 2024 the new rules on standards of quality and safety for substances of human origin for use on or in human recipients were published.
Substances of human origin (SoHO) means any substance collected from the human body.
These new rules will replace the current rules for blood Directive 2002/98 EC and tissues and cells Directive 2004/23/EC.
The types of products covered by these new rules has expanded. Previously unregulated substances, for example, faecal microbiota and human breast milk, are now included.
Most of the new rules will come into force from 7 August 2027, but some rules won’t come into force until 2028.
The HPRA will develop guidelines to include the registration process, how to maintain compliance and other relevant information as part of the implementation plan.
United States of America
The US Food and Drug Administration (USFDA)
Postapproval manufacturing changes to biosimilar and interchangeable biosimilar products Q&A
This guidance provides answers to commonly asked questions from applicants and other interested parties regarding postapproval manufacturing changes made to licensed biosimilars and licensed interchangeable biosimilars.
Applicants must inform FDA about each change in the product, production process, quality controls, equipment, facilities, or responsible personnel, established in the approved biologics license application (BLA). Before distributing a product made using a change, an applicant must assess the effects of the change and demonstrate through appropriate validation and/or other clinical and/or nonclinical laboratory studies the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product, as these factors may relate to the safety or effectiveness of the product
Real-World Data: assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products
FDA is issuing this guidance as part of its Real-World Evidence (RWE) program and to satisfy, in part, the mandate under the Federal Food, Drug, and Cosmetic Act (FD&C Act) to issue guidance about the use of RWE in regulatory decision making. This guidance is intended to provide sponsors and other interested parties with considerations when proposing to use electronic health records (EHRs) or medical claims data in clinical studies to support a regulatory decision for effectiveness or safety. This guidance finalizes the draft guidance of the same title issued on September 30, 2021.
This guidance complements the 2013 guidance by expanding on certain aspects of that guidance relating to the selection of data sources, and provides additional guidance for evaluating the relevance and reliability of both EHRs and medical claims data for use in a clinical study.
This guidance also provides a broader overview of considerations relating to the use of EHRs and medical claims data in clinical studies more generally, including studies intended to inform FDA’s evaluation of product effectiveness.
Addressing misinformation about medical devices and prescription drugs Q&A
This draft Guidance for Industry responds to common questions firms may have when voluntarily addressing misinformation about or related to their approved/cleared medical products. In addition to describing already existing avenues for communications by firms, this guidance sets out an enforcement policy for certain kinds of internet-based communications that firms might choose to use to address internet-based misinformation about or related to the firm’s approved/cleared medical product when that misinformation is created or disseminated by an independent third party.
The recommendations and illustrative examples in this guidance are intended to help support firms that choose to address misinformation about or related to their approved/cleared medical products.
International
Australia
Therapeutic Goods Administration (TGA)
Australian Sunscreen Exposure Model
This consultation is about creating a model that more accurately estimates how much sunscreen Australians are exposed to on a regular basis. The model will enable the TGA to calculate the safe concentration of ingredients in sunscreens based on Australian conditions and the latest scientific information.
Stakeholders have an opportunity to provide feedback on the best way to estimate sunscreen use in Australia, as well as any positive and negative impacts the proposals may have on businesses, professionals and consumers.
TGA invites you to provide your feedback by answering the questions in this consultation paper at the TGA consultation hub by 13 August 2024.
Business surrender scheme for vaping goods
To support the Government’s reforms to the regulation of vaping goods in Australia, transitional arrangements have been put in place. These arrangements allow businesses holding vaping goods that can no longer be supplied in Australia to divest themselves of these products without committing a supply or possession offence.
The Business Surrender Scheme allows businesses to surrender specified quantities of vaping goods that were lawful prior to 1 July 2024 but that are no longer lawful following the commencement of the Therapeutic Goods and Other Legislation Amendment (Vaping Reforms) Act 2024 on 1 July 2024.
The scheme is available to businesses possessing more than 280 vaping devices or 1,800 vaping accessories, or 12,000mL of vaping substance.
[a sensible looking approach to this issue. MBH]
Telehealth businesses fined over $300,000 for alleged unlawful advertising of weight loss medicines
The TGA issued 21 infringement notices totalling $319,260 to 4 businesses and 3 individuals for the alleged unlawful advertising of prescription-only medicines, primarily for weight loss, on their websites. Advertising prescription-only medicines directly to consumers is prohibited under the Therapeutic Goods Act 1989. as it could create an inappropriate demand for these medicines and lead to unnecessary or harmful prescribing.
Since 2022, the TGA has issued several warnings that advertising Ozempic is prohibited. Further, Ozempic is only approved by the TGA for lowering blood sugar in adults with type 2 diabetes and cannot be advertised to treat any other conditions.
The TGA reminds businesses that unlawful advertising of prescription-only medicines is a breach of the Act, for which significant penalties can apply, including fines, civil or criminal court action.
Pharmaceutical Inspection Co-operation Scheme (PIC/S
2024 PIC/S Seminar (Brasilia, Brazil)
Registrations are now open (for Medicines Regulatory Authorities only).
The National Health Surveillance Agency (ANVISA) will host the 2024 PIC/S Seminar on “Annex I Unveiled: Shaping the Future of Sterility” in Brasilia (Brazil) from 6-8 November 2024, preceded by the PIC/S Committee meeting.
The Seminar is the main annual international training event by PIC/S which is open to GMP Inspectors from PIC/S Participating Authorities, (Pre-)Applicants, Partners and non-PIC/S Member Medicines Regulatory Authorities.
Documents
FTC Releases Interim Staff Report on Prescription Drug Middlemen (PDM)
This USA Federal Trade Commission (FTC) Report details how prescription drug middleman profit at the expense of patients by inflating drug costs and squeezing Main Street pharmacies
The interim staff report, which is part of an ongoing inquiry launched in 2022 by the FTC, details how increasing vertical integration and concentration has enabled the six largest PBMs to manage nearly 95 percent of all prescriptions filled in the United States. This vertically integrated and concentrated market structure has allowed PBMs to profit at the expense of patients and independent pharmacists, the report details.
The report finds that PBMs wield enormous power over patients’ ability to access and afford their prescription drugs, allowing PBMs to significantly influence what drugs are available and at what price. This can have dire consequences, with nearly 30 percent of Americans surveyed reporting rationing or even skipping doses of their prescribed medicines due to high costs, the report states.
The interim report also finds that PBMs hold substantial influence over independent pharmacies by imposing unfair, arbitrary, and harmful contractual terms that can impact independent pharmacies’ ability to stay in business and serve their communities.
[Certainly not strictly a Regulatory GMP matter, but in the current climate of medicine shortages and eyewatering prices for some medicines particularly in the USA I thought that like me, some of our readers would be interested and find the report informative. MBH]
Products
Ocrelizumab approved as an injection to treat multiple sclerosis in adults
The UK MHRA has approved a new formulation of the medicine ocrelizumab (Ocrevus 920mg solution for injection) to treat relapsing forms of multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) in adults.
Ocrelizumab can be used in two types of patients:
· Adults with RMS, where the patient has flare-ups (relapses) followed by periods with mild or no symptoms;
· Adults with PPMS, where symptoms get steadily worse over time.
The active ingredient ocrelizumab was previously approved in the United Kingdom in 2018, administered as an infusion (drip) into a vein. The first two infusions are given two weeks apart and subsequent infusions every six months.
The approval of this formulation will enable patients to receive a total dose of 920mg of Ocrevus every six months, administered by a doctor or nurse as a subcutaneous injection.
[another treatment for a serious medical condition switching from an infusion to a subcutaneous injection – with obvious convenience, time and cost benefits for patient and healthcare provider. MBH]
Capivasertib approved to treat patients with advanced breast cancer
MHRA has approved the medicine capivasertib (Truqap) for patients with advanced hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer which has one or more abnormal “PIK3CA”, “AKT1”, or “PTEN” gene, and does not respond to other anti-hormonal-based therapies. The active substance capivasertib is part of a group of medicines called AKT inhibitors. Capivasertib is given with fulvestrant, a hormonal therapy for the treatment of advanced breast cancer.
The application for approval was supported by evidence obtained via a clinical trial of 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer, of which 289 patients had tumours with an abnormal PIK3CA, AKT1 or PTEN gene.
Vibegron (Obgemsa) to treat the symptoms of overactive bladder (OAB) syndrome in adults.
The UK MHRA has approved the medicine vibegron (Obgemsa) to treat the symptoms of overactive bladder (OAB) syndrome in adults.
The medicine’s active ingredient, vibegron, is a bladder muscle relaxant (a beta‑3 adrenergic receptor agonist) which reduces the activity of an overactive bladder and treats the related symptoms. The recommended dosage for this is 1 tablet per day.
This approval is supported by evidence from a phase 3 clinical trial. The EMPOWUR trial was used to evaluate vibegron over a period of 12 weeks in 1,515 patients with OAB syndrome and demonstrated symptoms of urgency and urinary frequency, with or without urge urinary incontinence. The results showed that compared to the placebo, vibegron was effective in treating symptoms of OAB syndrome. Daily urination and incidents of incontinence were reduced in patients with OAB syndrome. This was observed within two weeks of the trial and was shown to be constant throughout the 12-week period of treatment. The outcomes of the study suggested that the effects of the medicine are maintained after 52 weeks of treatment.
[Approved after a 12 week phase 3 clinical trial. Pretty impressive in respect of both outcome and timelines MBH]
MHRA approves the first generic raltegravir medicines to treat adult and paediatric patients infected by HIV
MHRA has, approved the first generic raltegravir medicines to treat adult and paediatric HIV patients who weigh at least 40kg.
The Human Immunodeficiency Virus (HIV) causes Acquired Immune Deficiency Syndrome (AIDS). HIV produces an enzyme called HIV integrase which enables multiplication of the virus in cells within the body. Raltegravir stops this enzyme from working, and when used with other medicines it may reduce the amount of HIV in the patient’s blood and increase the patient’s CD4-cell count
The active ingredient raltegravir is an antiviral medicine prescribed as a 600mg film‑coated tablet. The recommended dosage for the medicine is 1,200 mg as two 600 mg tablets taken orally once a day. Raltegravir must be used in combination with other medicines for HIV.
MHRA approves GLP –1 receptor agonist semaglutide to reduce risk of serious heart problems in obese or overweight adults
MHRA has approved a new indication for semaglutide (Wegovy) to reduce the risk of overweight and obese adults suffering serious heart problems or strokes.
The approval means that semaglutide is the first weight loss drug to be prescribed to prevent cardiovascular events, such as cardiovascular death, non-fatal heart attack and non-fatal stroke, in people with established cardiovascular disease and a Body Mass Index (BMI) higher or equal to 27 kg/m2.
EMA confirms its recommendation to update the antigenic composition of authorised COVID-19 vaccines for 2024-2025
The EMA Emergency Task Force (ETF) recommended to adapt vaccines to target the JN.1 family of Omicron subvariants to ensure cross-reactivity against the dominant strain (JN.1) and emerging strains and to increase the breadth of immunity against descendent lineages. Vaccine compositions targeting JN.1 subvariants could be considered if there was adequate justification. During its June plenary meeting, the CHMP recommended authorising an adapted Comirnaty vaccine targeting the JN.1 subvariant. The EC decision was expedited on 3 July 20243.
Spikevax, Nuvaxovid and Bimervax vaccines targeting JN.1 are under evaluation by the CHMP.
EMA was made aware of one potential regulatory submission to update the vaccine composition to target the KP.2 subvariant. KP.2 vaccines have been recommended by other jurisdictions, where feasible, and could therefore also become available for distribution where needed in the EU, subject to EMA approval.
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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