Review of Developments in GMP and the Regulation of Medicines March 2023
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INTRODUCTION
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, US, PIC/S ICMRA and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
Medicines and Healthcare Regulatory Authority (MHRA)
Impact of extension of Medical Device Regulations transitional period and the validity of certificates in the EU
MHRA safety review of medicines containing pseudoephedrine
2023 work plan for the Quality Innovation Group (QIG)
A new role for EMA in monitoring and mitigating critical medical device shortages during public health emergencies
Public consultation on a multi-stakeholder platform to improve clinical trials in the EU
Actions to support the development of medicines for children
Bioequivalence for immediate-release solid oral dosage forms M13A
4th meeting of the Nitrosamine Implementation Oversight Group (NIOG).
ICH guideline Q9 (R1) on quality risk management Step 5
Human Medicines Highlights issue 166
Adjuvants in vaccines for human use - Scientific guideline
Guideline on plasmid DNA vaccines for veterinary use
EMA pilots scientific advice for certain high-risk medical devices
Outcome of recent EDQM EPAA meeting on pyrogenicity testing.
Public consultation on Ph. Eur. rabbit pyrogen test replacement texts in Pharmeuropa 35.1
Ph. Eur. Commission establishes a dedicated working party on High Throughput Sequencing
Ph Eur Reference Standards
Public consultation on two chapters on pharmaceutical technology procedures
SNOMED International and the EDQM collaborate on map development
Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA
Australia
Therapeutic Goods Administration(TGA)
Sport supplement suppliers to check products for latest WADA banned substances
Second bivalent COVID-19 booster vaccine from Moderna (Spikevax) authorised by UK medicines regulator
Summary report of the Joint EMA-FDA workshop on the efficacy of monoclonal antibodies in the context of rapidly evolving SARS-CoV-2 variants
The EU and UK have a Northern Ireland deal — so what’s in it?
Medicines
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Impact of extension of Medical Device Regulations transitional period and the validity of certificates in the EU
The EU Commission has voted to adopt an extension of the transition period for the EU Medical Device Regulations and to extend the validity of certain device certificates
The proposal recognises the challenges in capacity across notified bodies. These changes made to the EU MDR will apply automatically in Northern Ireland under the terms of the Northern Ireland Protocol.
The MHRA is working to consider carefully what the implications of these revisions are for acceptance of CE marked medical devices on the Great Britain (GB) market. At present, a device with a valid CE mark can be placed on the GB market until 30 June 2023. That includes certificates valid under the latest EU’s revised transitional arrangements.
The MHRA has an exceptional use authorisation (EUA) process in place, that enables devices to be placed on the market in limited circumstances, when they do not have a valid CE or UKCA mark, including where those marks have expired.
MHRA safety review of medicines containing pseudoephedrine
The MHRA is reviewing the evidence relating to the very rare risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) associated with medicines containing pseudoephedrine.
Pseudoephedrine is used for the symptomatic relief of coughs, colds and allergies. Pseudoephedrine has been used in the UK for decades in millions and millions of people. MHRA is reviewing the available evidence relating to the very rare risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) associated with pseudoephedrine-containing medicines. Since these products were authorised, we have received two UK Yellow Card reports of these possible side effects associated with pseudoephedrine, despite very widespread usage. The potential risk is considered to be very rare.
Europe
European Medicines Agency (EMA)
2023 work plan for the Quality Innovation Group (QIG)
Pharmaceutical manufacturing is undergoing profound changes supported by latest advances in novel technologies (e.g., continuous manufacturing, personalised medicines, 3D printing), analytics and data processing including digitalisation and increased automation.
The need for more agile manufacturing approaches and supply chains aims to bring new therapies to patients more rapidly and/or to improve supply and resilience in pharmaceutical manufacturing.
Adopting these innovative technologies may present both technical and regulatory challenges to industry and regulators. Taking into account the background information available and relevant information from the NCAs), the QIG has identified priority topics for 2023. These are proposed and listed together with their Focus area and challenges.
Challenges have been identified from interactions with industry and literature review; further dialogue with stakeholders is required to fully understand the CMC and GMP challenges faced, discuss which could be addressed by the QIG.
A new role for EMA in monitoring and mitigating critical medical device shortages during public health emergencies
As of 2 February 2023, EMA’s additional responsibilities regarding the monitoring and mitigation of shortages of critical medical devices during public health emergencies will apply. The Agency is now responsible for coordinating responses of EU / EEA countries to shortages of critical medicines and medical devices including in-vitro diagnostics during public health emergencies. The Medical Devices Shortages Steering Group (MDSSG) will be set up to coordinate urgent actions within the Union in relation to the management of supply and demand issues of critical medical devices and to make recommendations to relevant stakeholders, including the European Commission, Member States and notified bodies.
Once established, the MDSSG will be responsible for adopting lists of medical devices which it considers to be critical for declared public health emergencies. These lists come with new reporting obligations for manufacturers of medical devices, authorised representatives and, if required, also for importers, distributors and notified bodies of those critical medical devices. Together with information from Member States this will enable accurate monitoring of the supply of and demand for these devices so that measures to prevent or mitigate potential and actual shortages can be taken swiftly and in a coordinated manner.
Public consultation on a multi-stakeholder platform to improve clinical trials in the EU
On 3 February 2023, EMA, the Heads of Medicines Agencies (HMA) and the European Commission (EC) are launching a public consultation on the establishment of a multi-stakeholder platform to improve clinical trials in the European Union (EU).
Successful clinical trials require the collaboration of a wide range of stakeholders. The creation of a common platform will encourage interactions between stakeholders at EU level, promoting a shared understanding and enabling concerted action to improve the clinical trials landscape for the benefit of innovation and all European citizens. Stakeholders are invited to send their comments on the concept paper, advise on the key priorities for discussion and express their interest to join the platform until 3 March 2023.
Experience with the COVID-19 pandemic has demonstrated the need to accelerate change and innovation in the way that clinical trials are designed, regulated, and conducted to maximise their efficiency and improve patient access to treatments.
Actions to support the development of medicines for children
Regulators in the European Union (EU) have taken several initiatives in the past four years to increase the efficiency of paediatric regulatory processes and boost the development of medicines for children.
Some of the key improvements brought by the paediatric action plan include:
Strengthened focus on unmet medical needs
Adapting regulatory processes to better support innovation
Increased alignment of data requirements between decision-makers
The Paediatric Regulation came into force in the EU in 2007 to encourage manufacturers to research and develop medicines for children’s specific therapeutic needs by using a system of rewards and obliging developers to specifically plan the development of their medicine for children (e.g. by integrating it into the development for adults) and submit a corresponding PIP. A PIP is a development plan aimed at ensuring that the necessary data are obtained through studies in children, to support the authorisation of a medicine for paediatric patients. All applications for marketing authorisation for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver.
ICH Guideline M13A on bioequivalence for immediate-release solid oral dosage forms - Scientific guideline
ICH M13A guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.
The ICH M13A guideline is the first guideline in a foreseen ICH series describing the scientific and technical aspects of study design and data analysis to support BE assessment for orally administered IR solid oral dosage forms. For more information on harmonisation of BE, please refer to the dedicated ICH M13 page.
Currently, the anticipated finalisation date of ICH M13A is May 2024. Once finalised, the CHMP will implement it as a European guideline superseding the EMA guideline on the investigation of bioequivalence for these oral dosage forms. Note Appendix III of the EMA guideline is already superseded by the ICH M9 guideline on biopharmaceutics classification system-based biowaivers.
The consultation period closes 26 May 23
4th meeting of the Nitrosamine Implementation Oversight Group (NIOG).
Documents, including presentations from industry and highlights were published by EMA on 7 Feb 2023
ICH guideline Q9 (R1) on quality risk management Step 5
This document received final adoption by EMA’s Committee for Medicinal Products for Human Use (CHMP) and will come into effect on 26 July 2023.
Human Medicines Highlights issue 166
This newsletter is addressed primarily to organisations representing patients, consumers and healthcare professionals. It provides a summary of key information relating to medicines for human use published during the previous month by the European Medicines Agency. Information is selected based on recommendations from consulted patients, consumers and healthcare professionals, and does not necessarily cover all relevant information published by the Agency.
Adjuvants in vaccines for human use - Scientific guideline
This document addresses the quality issues arising from the use of new or established adjuvants in vaccines. The applicability of this guideline to established adjuvants will vary on case-by-case basis.
Adjuvants that are given separately and/or at a different time point from the vaccine antigens are not considered to be adjuvants and are called immunomodulators.
EMA will not update this guideline as its clinical and non-clinical sections have been superseded by the:
Scientific guideline on the clinical evaluation of new vaccines;
WHO guideline on non -clinical evaluation of vaccines.
Applicants can still use the quality section of this guideline, as it remains valid.
Guideline on plasmid DNA vaccines for veterinary use
The aim of the guideline is to outline the information which should be included for plasmid DNA vaccines in the marketing authorisation application (MAA) dossier of veterinary vaccines as required in Section IIIb (Requirements for immunological veterinary medicinal products) of the Commission Delegated Regulation (EU) 2021/805 amending Annex II to Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products (repealing Directive 2001/82/EC), referred to as Annex II to Regulation (EU) 2019/6 throughout the document.
The use of DNA for vaccination has progressed in the last few years and several trials using products of this type for vaccination are in progress. DNA vaccination involves the inoculation with (a) gene(s) encoding (a) relevant antigen(s) against which an immune response is desired. The gene(s) can be under the control of a promoter, which will permit its expression in the vaccinated animal. This gene construct may be contained, for manipulation and manufacturing purposes, within plasmid DNA (bacterial plasmid DNA or de novo synthetic DNA).
Readers will probably be most interested in Section 5.1 - Data requirements for Part 2 Quality.
The deadline for comments on this draft is 23 June 2023
EMA pilots scientific advice for certain high-risk medical devices
EMA has launched a pilot to give scientific on the intended clinical development strategy and proposals for clinical investigation for certain high-risk medical devices (intended to administer and/or remove medicinal product (s)). Manufacturers can submit their letter of interest to be part of the pilot. Expert panels will provide free advice to ten selected applicants on their clinical development strategy and/or proposals for clinical investigation. The pilot will last approximately one year
The pilot will prioritise certain types of medical devices:-
devices that benefit a small group of patients in the treatment or diagnosis of a disease or condition, such as devices intended for the treatment of a rare condition, known as ‘orphan devices’, and devices for paediatric use;
devices addressing medical conditions that are life threatening or cause permanent impairment of a body function and for which current medical alternatives are insufficient or carry significant risks;
novel devices with a possible major clinical or health impact.
EDQM
Outcome of recent EDQM EPAA meeting on pyrogenicity testing.
EDQM and the European Partnership for Alternative Approaches to Animal Testing (EPAA) have just held a highly successful three-day joint event aimed at phasing out the rabbit pyrogen test (RPT) from the testing of pharmaceuticals worldwide.
On the second day of the conference, regulators from Europe and around the world shared their views on the replacement of the RPT. They all welcomed submissions of in vitro pyrogen tests and look forward to receiving an increasing number of dossiers with the appropriate validation data. International collaboration will be key to the wider acceptance of the MAT worldwide.
Pharmacopoeias from other regions (Brazil, China, India, Japan, United States) also joined the event and all committed to progressively phase out animal tests from their respective standards, including the RPT. For some of these organisations, this will take time but the commitment is there. It was extremely interesting to learn, from the World Health Organization representative present at the conference, that a similar path – promoting the MAT over the RPT – will be followed on a worldwide level.
Public consultation on Ph. Eur. rabbit pyrogen test replacement texts in Pharmeuropa 35.1
The European Pharmacopoeia (Ph. Eur.) has published the 59 texts (1 new general chapter, 5.1.13. Pyrogenicity, and 58 revised texts) concerned by the rabbit pyrogen test (RPT) replacement strategy for public consultation in Pharmeuropa 35.1, with a commenting deadline of 31 March 2023.
These texts have been revised to replace the RPT with an in vitro alternative, the monocyte activation test (MAT) or another animal welfare-compatible approach.
Ph. Eur. Commission establishes a dedicated working party on High Throughput Sequencing
At its 174th session in November 2022, the European Pharmacopoeia (Ph. Eur.) Commission decided to create a new Working Party on High Throughput Sequencing (HTS), in charge of elaborating a general chapter on HTS for the detection of viral extraneous agents. Also known as NGS, this advanced technology has broad virus detection capability and the new general chapter should facilitate its use as a new analytical tool to ensure the viral safety of biological medicines.
Specialists with expertise in HTS for the detection of extraneous agents in biologicals and in the development and validation of analytical procedures based on HTS are invited to apply to join the new Working Party on this important journey to develop a quality standard for HTS.
[Note specialists from industry are included in this invitation. – A valuable opportunity. MBH]
Ph Eur Reference Standards
24 replacement batches released in January 2023.
Public consultation on two chapters on pharmaceutical technology procedures
Two texts dealing with pharmaceutical technology, one revised and one new, have recently been published in Pharmeuropa 35.1 for public consultation.
Revision of the harmonised general chapter 2.9.3. Dissolution of tablets and capsules
The text on dissolution testing of oral solid dosage forms has been revised essentially to provide a more detailed description of the two possible ways of operating Apparatus 3 – reciprocating cylinder.
New general chapter 2.9.55. Characterisation of powder behaviour during compression
Powder compression is a critical process in tablet manufacturing. Problems during compression are numerous. It is important to characterise tablet compression in order to control the compression process well.
The detailed new general chapter on characterisation of powder behaviour during compression provides guidance for standardised compression test procedures such as evaluation of compressibility, tabletability and compactibility profiles.
SNOMED International and the EDQM collaborate on map development
SNOMED International and the EDQM, Council of Europe, have signed an agreement governing the creation, maintenance and distribution of a map between both organisations’ terminologies. The agreement came into effect in September 2022. The agreement resulted from the need identified by SNOMED International’s Drug Extension User Support Group to align EDQM Standard Terms and SNOMED CT dose forms to serve specific use cases.
The Alpha release of the EDQM Standard Terms to SNOMED CT map package for dose forms was made available by SNOMED International in early January 2023. A spreadsheet format has also been made available for those who want to review the map. Feedback received from the Alpha release will be incorporated into the Production release of the map package in Q2 of 2023, followed by annual releases. Both organisations will review the conditions of the agreement every five years.
(Note - SNOMED International is a not-for-profit organisation that owns and develops SNOMED CT, the world's most comprehensive healthcare terminology product. The European Pharmacopoeia Commission comprises 40 members and the Council of Europe currently has 46 Member States)
United States of America
The US Food and Drug Administration (USFDA)
Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA
This guidance provides recommendations to industry on product-specific guidance (PSG) meetings between FDA and a prospective applicant preparing to submit to FDA or an applicant that has submitted to FDA an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). Specifically, this guidance provides information on requesting and conducting PSG meetings with FDA (PSG teleconferences, pre-submission PSG meetings, and post-submission PSG meetings), as contemplated in the Generic Drug User Fee Amendments (GDUFA) Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). And this guidance is intended to provide procedures that will promote well-managed PSG meetings and help ensure that such meetings are scheduled and conducted in accordance with the time frames set forth in the GDUFA III commitment letter.
International
Australia
Therapeutic Goods Administration(TGA)
Sport supplement suppliers to check products for latest WADA banned substances
Suppliers of sport supplements in Australia are encouraged to check World Anti-Doping Code International Standard Prohibited List (WADA)’s 2023 Prohibited List ahead of an update to the Therapeutic Goods (Declared Goods) Order 2019 (Declared Goods Order) on 1 March 2023.
This is the first time since 2020 that the Declared Goods Order has been amended to capture an update to the Prohibited List. Thirty-one ingredients have been added to the Prohibited List since 2020, most of which are contained within the Australian Poisons Standard and are therefore already captured by the Declared Goods Order. The ingredients not included in the current Poisons Standard have been assessed to be for therapeutic use, and therefore their inclusion in a sports supplement product means they are a therapeutic good under Therapeutic Goods Act 1989. The TGA encourages sports supplement product manufacturers, sponsors, retailers, and advertisers to review the 2023 Prohibited List against their product range and take action to ensure their products comply with the law.
Products
Second bivalent COVID-19 booster vaccine from Moderna (Spikevax) authorised by UK medicines regulator
This adapted COVID-19 vaccine targets both the original coronavirus (SARS-CoV-2) and the Omicron BA.4 and BA.5 sub-variants.
In each dose, half of the vaccine targets the original virus strain and the other half targets Omicron (BA.4 and BA.5).
Summary report of the Joint EMA-FDA workshop on the efficacy of monoclonal antibodies in the context of rapidly evolving SARS-CoV-2 variants
There was overall agreement on the need to expedite the development of new monoclonal antibody products against emerging variants of concern (especially in the context of pre-exposure prophylaxis for immunocompromised patients), with an understanding that demonstrating safety in humans for any new product remains essential. There was general support for the use of a biomarker approach based on immunobridging (GMT of neutralising antibodies at specific timepoints) preferably with a combination of PK modelling and confirmation of clinical efficacy post-approval/post-authorisation. Overall, participants did not believe that a cross-variant comparison would be significantly impacted by assay constraints, if it is ensured that assay performance criteria, i.e., linearity, range, precision, slope and response, are comparable. The need for post-marketing efficacy data, i.e., the investigation of breakthrough cases, monitoring of neutralising antibody and drug concentration to determine the timing of waning antibodies, and to support the surrogate markers of efficacy used for initial regulatory action was highlighted. Concerning the clinical trial designs for immunobridiging studies and the potential approach for collecting post-marketing efficacy data, it was agreed that further discussion with regulatory authorities is considered necessary. All participants agreed that the prevention of COVID-19 in immunocompromised patients should be a primary target of future monoclonal antibody development.
Documents
The EU and UK have a Northern Ireland deal — so what’s in it?
This article by Cristina Gallardo appeared on the POLITICO website on February 27, 2023 soon after the agreement was reached. Readers will be most interested in the section concerning medicines which states:-
Medicines
Drugs approved for use by the U.K.’s medicines regulator, the MHRA, will be automatically available in every pharmacy and hospital in Northern Ireland, “at the same time and under the same conditions” as in the U.K., von der Leyen said.
Businesses will need to secure approval for a U.K.-wide license from the MHRA to supply medicines to Northern Ireland, rather than having to go through the European Medicines Agency. The agreement removes any EU Falsified Medicines Directive packaging, labeling and barcode requirements for medicines. This means manufacturers will be able to produce a single medicines pack design for the whole of the U.K., including Northern Ireland.
Drugs being shipped into Northern Ireland from Great Britain will be freed of customs paperwork, checks and duties, with traders only being required to provide ordinary commercial information.
The EU’s safeguards: Medicines traveling from Great Britain to Northern Ireland will do so via the new green lane, which will have monitoring to protect the single market built in.
The timeline: The U.K. government said it will engage with the medicines industry soon on these changes.
[cautionary note - official confirmation from MHRA will be needed. MBH]
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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