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  • EJPPS

Review of Developments in GMP and the Regulation of Medicines July 2022


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Vol27.3A July 2022
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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, Australian, ICMRA and PIC/S regulatory authorities. Once again a number of specific product issues of particular interest have been included.


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


UK


Medicines and Healthcare Regulatory Authority (MHRA)

  • Guidance on handling of Decentralised and Mutual Recognition Procedures which are approved or pending

  • MHRA joins international partnerships to set global standards for medicines and medical devices regulation


EU

  • EMA annual activity report 2021

  • EMA Management Board meeting

  • EMA adopts first list of critical medicines for COVID-19

  • Checklist for annual updates for parallel distribution

  • Post-authorisation procedural advice for users of the centralised procedure.- Q&A

  • Call for companies to register their Industry Single Point of Contact (i-SPOC) on supply and availability

  • First industry standing group (ISG) meeting

  • European Veterinary Big Data strategy 2022- 2027

  • Faecal Microbiota Transplantation

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

  • Revision of Heparin sodium (0333) and Heparin calcium (0332) monographs – feedback required.

  • OMCL Annual Meeting 2022: European Strategies for Work Sharing and Collaboration in Testing of Medicines

  • 2021 Highlights – EDQM annual report


USA

  • Non-Penicillin Beta-Lactam Drugs: A CGMP framework for preventing cross-contamination

  • Q9(R1) Quality Risk Management

  • Considerations for rescinding breakthrough therapy


International


Australia

Therapeutic Goods Administration (TGA)

  • Uniform recall procedure for therapeutic goods (URPTG)

  • Medicinal cannabis reforms: Frequently asked questions

  • TGA is seeking feedback on whether or not certain international scientific guidelines should be adopted.

International coalition of medicines regulatory authorities (ICMRA)

  • Global regulators work towards strengthening collaboration on observational research beyond COVID-19 pandemic

Pharmaceutical Inspection Co-Operation Scheme (PIC/S)

  • 2022 workplan


Products

  • EMA recommends Valneva’s COVID-19 vaccine for authorisation in the EU

  • EMA recommends authorisation of Nuvaxovid for adolescents aged 12 to 17

  • Rolling review for adapted Spikevax COVID-19 vaccine

  • EMA recommends withdrawal of marketing authorisation for amfepramone obesity medicines

  • Monkeypox: EMA starts review for Imvanex

  • Hydroxyethyl-starch solutions for infusion recommended for suspension from the market- update



RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Guidance on handling of Decentralised and Mutual Recognition Procedures which are approved or pending

On 24 June a section was added to this guidance for 'Guidance for The Conversion of PLGB or PLNI licences to PL'

MHRA joins international partnerships to set global standards for medicines and medical devices regulation

These are the International Medical Device Regulatory Forum (IMDRF), the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the US based Medical Devices Innovation Consortium (MDICs).

IMDRF and the ICH are focused on improving the harmonisation and convergence of medicines and medical devices regulation globally. MDICs is a public-private partnership which brings together representatives of regulatory bodies, industry, non-profits, and patient organisations from different countries to improve the processes for development, assessment, and review of new medical technologies.



Europe


EMA

Annual activity report 2021

The consolidated annual activity report provides an overview of the activities and achievements of the (EMA) in 2021. The document a key component of the strategic planning and programming cycle and the basis upon which the EMA Executive Director takes their responsibility for the management of resources, and the achievement of objectives. It also allows the EMA Executive Director to decide on the necessary measures in addressing any potential management and control weaknesses identified. The annual activity report 2021 comprises five main parts and annex.

EMA Management Board meeting

EMA has published the highlights of its June 2022 management board meeting.

EMA adopts first list of critical medicines for COVID-19

The medicines included in the list are authorised for COVID-19 and their supply and demand will be closely monitored to identify and manage potential or actual shortages.

Given the current stage of the pandemic, the published list contains all the approved vaccines and therapeutics in the European Union (EU) to prevent or treat COVID-19. It will be updated to reflect changes in the pandemic situation which may give rise to an increased risk of shortages of particular medicines, or following the authorisation of new medicines. The list does not replace national guidance on vaccination and the clinical management of COVID-19.

Marketing authorisation holders (MAHs) of medicines included in the list are required to regularly update EMA with relevant information, including data on potential or actual shortages and available stocks, forecasts of supply and demand. In addition, Member States will provide regular reports on estimated demand for critical medicines at national level. This will enable the MSSG to recommend and coordinate appropriate EU-level actions to the European Commission and EU Member States in order to prevent or mitigate potential or actual shortages of critical medicines to safeguard public health. EMA will liaise individually with the MAHs and national competent authorities to inform them of the timelines, processes and tools to collect the required information following the adoption of the list.

Checklist for annual updates for parallel distribution

EMA has issued version 3 of this document and asks its applicants to use this checklist in advance of submission of an annual update for parallel distribution. You should be able to answer “Yes” to every item listed unless a specific point is not applicable (“n/a”) to the application in question. In order to improve the quality of submissions, it is recommended to include the checklist with your

submission.

Post-authorisation procedural advice for users of the centralised procedure. Q&A

EMA has issued revision 99 of this Q&A. Questions and answers are being updated continuously and will be marked by “NEW” or “Rev.” with the relevant date upon publication

Call for companies to register their Industry Single Point of Contact (i-SPOC) on supply and availability

Marketing Authorisation Holders (MAHs) can now register their Industry Single Point of Contact (i-SPOC) who will inform EMA about the supply and availability of critical medicines identified in the context of a ‘public health emergency’ or a ‘major event’ .

EMA’s role in crisis preparedness, includes the monitoring and management of medicine shortages that may lead to a crisis and, during a public health emergency or a major event, with the reporting of shortages, information on supply and demand, and coordinating responses of EU countries to shortages of critical medicines. All pharmaceutical companies with a centrally- or nationally-authorised medicinal product in the EU are required to register a single point of contact.

First industry standing group (ISG) meeting

This new forum started 21 June2022, in its pilot phase, with a restricted scope dedicated to industry stakeholders’ interactions to facilitate timely and efficiently EMA’s extended mandate. Specific topics related to the three main pillars of the EMA mandate extension were to be discussed: -

  • Emergency Task Force

  • Medicines & medical device shortages

  • Medical device expert panels status activities development updates and processes development of specific industry stakeholders impact.

European Veterinary Big Data strategy 2022- 2027

The European Medicines Regulatory Network (EMRN) is revising its procedures, and regulatory and scientific guidance and takes leadership in the implementation of new digital technology, as anticipated by the BDSG initiatives, throughout the whole live cycle of veterinary and human medicines, during development, registration and marketing. In the Veterinary area, this goes in parallel with the implementation of the revised Veterinary legislation where significant efforts have been invested for the implementation of new digital technology (IT) systems which will made available an increased amount of data across the EU Regulatory Network. Moreover, outside the regulatory environment, it is to be considered that the ongoing digital revolution will produce higher amount of data (e.g. sensor data in farm management and animal healthcare practises) offering the potential to unlock scientific knowledge and increase regulatory efficiency, responsiveness and robustness. It is therefore compelling that the Veterinary Regulatory Network is prepared to absorb and uptake the challenges and opportunities that digital transformation offers and continue building upon the overall goals set by the VMP-Reg of simplifying the regulatory environment, reduce administrative burden, stimulate the development of innovative veterinary medicines and improve the functioning of the internal market for veterinary medicines.

Faecal Microbiota Transplantation

While there is no universally accepted definition of Faecal Microbiota Transplantation (FMT), in general FMT refers to the transfer of biological material incorporating faecal microorganisms from screened, healthy human donors to the gastrointestinal tracts (GITs) of patients.

In some cases, there may also be autologous use. FMT is currently being investigated for the treatment of a number of different medical conditions, with one of the main uses being in the treatment of patients with recurrent Clostridioides difficile (C. difficile) infections (CDIs). In these patients, FMT aims to achieve modification of the composition of the microbiota in the large bowel, which, in turn, re-establishes normal bacterial competition mechanisms. The desired result is a reduction in numbers of toxigenic C. difficile, and so, reducing the risk of further recurrences.

Based on short term follow-up, FMT has generally shown a good safety profile provided that appropriate steps are taken to ensure quality and safety. However, further data from long-term monitoring of patients for adverse events are needed to fully evaluate the effects that donor’s intestinal microbes may have on FMT recipients and the potential for transmission of diseases.

[Readers may wish to look particularly at section 1.3 of the report which covers extemporaneous preparation and also ‘manufacture’ in dedicated facilities within research institutions or by pharmaceutical companies. MBH]


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

Revision of Heparin sodium (0333) and Heparin calcium (0332) monographs – feedback required.

First published in the 1980s, the monographs on unfractionated heparin are some of the earliest texts of the European Pharmacopoeia (Ph Eur). The most recent draft versions of the texts have just been published in Pharmeuropa 34.3 (July 2022). The Production section in these proposed drafts has been amended to clarify statements on the control for absence of non-porcine source materials, an aspect that was already the subject of a public enquiry in 2021 (Pharmeuropa 33.3). In addition, it is proposed to lower the current limit for residual protein from ≤ 0.5 per cent to ≤ 0.1 per cent, a level considered more commensurate with a substance that is used in parenteral products. The Ph. Eur. would like to encourage all stakeholders to provide feedback on the draft heparin monographs by 30 September 2022

OMCL Annual Meeting 2022: European Strategies for Work Sharing and Collaboration in Testing of Medicines

Highlights of the General Session of the Annual Meeting included a presentation by representatives from the Malta Medicines Authority, participating in the meeting for the first time, on Malta’s current project to set up an OMCL on their territory. Participants in the general session also discussed action taken around the four strategic network goals, which included examples of activities of specialised centres (such as those related to the nitrosamine incidents) and intensified collaboration between OMCLs and inspection services at national level.

Specialised activities addressed at the General Session included the use of mass spectrometry in OMCLs for the testing of biotherapeutics and small molecule medicines, for example in cases of suspected falsification, to support quality defect reports and GMP findings or in connection with the detection and quantification of mutagenic impurities in medicines. The implementation in OMCLs of rules on measurement uncertainty was addressed in the quality assurance part of the programme, as well as the pros and cons of remote audits.

2021 Highlights – EDQM annual report

The 2021 annual report of the (EDQM) is now available, providing a comprehensive overview of its activities and achievements. New to this edition is a four-page summary of key facts and figures in the introductory section, allowing readers to find essential information about 2021 at a glance.

The EDQM continued to fulfil its mission to protect public health last year, both despite and because of the global pandemic and its impact on the quality of medicines and healthcare.



United States of America


The US Food and Drug Administration (USFDA)

Non-Penicillin Beta-Lactam Drugs: A CGMP framework for preventing cross-contamination

This guidance describes methods, facility design elements, and controls that are important in preventing drugs from being cross-contaminated with compounds containing a beta-lactam ring.

This guidance also provides information regarding the relative health risk of, and the potential for, cross-reactivity in the classes of non-penicillin beta-lactam antibacterial drugs and non-antibacterial beta-lactam compounds.

This guidance recommends complete and comprehensive separation of the manufacturing operations of non-penicillin beta-lactam antibacterial drugs from the manufacturing operations of other drugs.

For manufacturers of non-antibacterial beta-lactam compounds, this guidance provides recommendations on cross-contamination prevention strategies, including examples of relevant design features and control approaches for those seeking to justify a cross-contamination prevention strategy other than complete and comprehensive separation when appropriate.

Comments should be submitted by 23 Aug 2022.

Q9(R1) Quality Risk Management

FDA has published this ICH document for comment by 15 July 2022

Considerations for rescinding breakthrough therapy

This guidance explains how, during its evaluation of a drug development program, FDA may consider whether to rescind a breakthrough therapy designation (BTD). The BTD program is intended to facilitate and expedite the development of those drugs that receive designation and involves a resource commitment from FDA to provide early and frequent advice, conduct multidisciplinary meetings involving senior managers, and when appropriate, expedite the review of resultant marketing applications. Thus, it is important that available evidence continues to fulfil the standards for BTD. The information supporting the granting of BTD for a particular drug may change over time. Some drugs that appear promising in early development may not be shown to be safe or effective in later trials, or the magnitude of a treatment effect suggested by early development may not be observed in later stages of development. Accordingly, given the resource-intensive nature of the BTD program, and in keeping with the Agency’s authority to grant BTD only to drugs that meet the legal criteria, FDA periodically assesses whether designated products continue to meet the criteria for BTD.



International


International coalition of medicines regulatory authorities (ICMRA)

Therapeutic Goods Administration (TGA)

Uniform recall procedure for therapeutic goods (URPTG)

A new version of the Uniform Recall Procedure for Therapeutic Goods (URPTG) (V2.3, June 2022) has been implemented, with effect from 30 June 2022.

This version includes the following updates:

  • Removal of the references to the Crisis Management Guidelines

  • Clarification on the submission of customer/distribution lists, including an example list in the appropriate format

  • Additional guidance related to the online notification of actions through the TGA Business Services (TBS) website. For further user information about the online notification form, open the tab below

  • Clarification on the submission of final reports, including additional guidance regarding root cause, CAPA information, customer follow-up attempts, and TGA close out letters

  • Minor changes to the information on consumer recall notices, including targeted SMS alerts and clarification on website publication timeframes

This version also includes a number of other minor editorial amendments.

Medicinal cannabis reforms: Frequently asked questions

In recent years, there has been a significant increase in the supply and use of medicinal cannabis products in Australia. In light of this, the TGA undertook a review of the regulation of these medicines to ensure it was still fit for purpose. This review included a public consultation held between December 2020 and January 2021. The changes implemented take into account feedback received during the consultation.

TGA is seeking feedback on whether or not certain international scientific guidelines should be adopted.

The TGA has approximately 370 current adopted international scientific guidelines.

TGA closely aligns its regulatory approaches to therapeutic products with those of comparable international regulatory counterparts wherever possible.

Technical data requirements for applications to register or vary the registration of medicines in Australia are closely aligned with requirements set out in relevant:

  • European Union (EU) Guidelines

  • Guidelines issued by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use

  • USA Food and Drug Administration (FDA) Guidelines

TGA are now seeking feedback on whether or not certain international scientific guidelines, as detailed in an online survey, should be adopted


International coalition of medicines regulatory authorities (ICMRA)

Global regulators work towards strengthening collaboration on observational research beyond COVID-19 pandemic

Lessons learned from international collaboration on observational research during the pandemic were highlighted during the latest global regulatory workshop on COVID-19 observational studies and real-world data. International regulators are working together to enhance global capabilities for observational research in the context of the COVID-19 pandemic and beyond. Real-world evidence generated from observational research is critical to understanding the safety and effectiveness of medicines when used in clinical practice for the prevention and treatment of COVID-19. Workshop participants discussed the results of three technical ICMRA working groups that focus on vaccines surveillance and vigilance, pregnancy observational research and the building of international cohorts of patients. They acknowledged the importance of these platforms that allow timely sharing of data, experience and tools, which can benefit patients globally. Medicines regulators from around the world also shared their experience of performing observational studies based on real-world data in the context of COVID-19 and discussed key lessons learnt during the public health emergency.

Pharmaceutical Inspection Co-Operation Scheme (PIC/S)

2022 workplan

The PIC/S work plan for 2022 has been published.



Products

EMA recommends Valneva’s COVID-19 vaccine for authorisation in the EU

COVID-19 Vaccine (inactivated, adjuvanted) Valneva contains inactivated (killed) whole particles of the original strain of SARS-CoV-2 that cannot cause disease. It is the sixth vaccine recommended in the EU for protecting against COVID-19The main study conducted with Valneva’s vaccine is an immunobridging trial. Immunobridging trials compare the immune response induced by a new vaccine with that induced by an authorised comparator vaccine proven to be effective against the disease. Based on the data provided, it was not possible to draw any conclusion on the immunogenicity of Valneva’s vaccine (its ability to trigger the production of antibodies) in people above 50 years of age; therefore, the vaccine is currently recommended only for use in people between 18 and 50 years of age. There are limited data on the immunogenicity of COVID-19 Vaccine (inactivated, adjuvanted) Valneva against variants of concern, including Omicron subvariants which are currently the dominant strains in many EU countries. The European Commission will now fast-track the decision-making process to grant a decision on the standard marketing authorisation for COVID-19 Vaccine (inactivated, adjuvanted) Valneva, allowing this vaccine to be included in vaccination programmes rolled out across the EU.

EMA recommends authorisation of Nuvaxovid for adolescents aged 12 to 17

EMA’s human medicines committee (CHMP) has recommended granting an extension of indication for the COVID-19 vaccine Nuvaxovid to include use in adolescents aged 12 to 17 years. The vaccine, developed by Novavax CZ, a.s., is already approved for use in adults aged 18 and above.

Rolling review for adapted Spikevax COVID-19 vaccine

EMA has started a rolling review for a version of Spikevax adapted to provide better protection against specific variants of SARS-CoV-2. The review concerns a bivalent vaccine. This means it will target two strains of SARS-CoV-2, in this case the original strain and the Omicron variant of concern.

The review will continue until there is enough data for a formal application. This rolling review process is one of the ways authorities in the EU are working to ensure that EU Member States have timely access to adapted COVID-19 vaccines they may need to combat current and emerging SARS-CoV-2 variants.

EMA recommends withdrawal of marketing authorisation for amfepramone obesity medicines

The recommendation by EMA’s safety committee (PRAC) follows a review which found that measures to restrict the use of these medicines for safety reasons have not been sufficiently effective. It found that the medicines were being used for longer than the recommended maximum period of 3 months, thereby potentially increasing the risk of serious side effects, such as pulmonary arterial hypertension (high blood pressure in the arteries of the lungs) and dependency. The medicines were also being used in patients with a history of heart disease or psychiatric disorders, increasing their risk of heart and psychiatric problems. In addition, there was evidence of use during pregnancy, which could pose risks to the unborn baby.

Monkeypox: EMA starts review for Imvanex

EMA’s CHMP has started a review of data to extend the use of the smallpox vaccine Imvanex to include protecting people from monkeypox disease.

Imvanex is currently authorised in the EU for the prevention of smallpox in adults. It contains a live modified form of the vaccinia virus called ‘vaccinia Ankara’, which is related to the smallpox virus. It is also considered a potential vaccine for monkeypox because of the similarity between the monkeypox virus and the smallpox virus.

Supplies of Imvanex are currently very limited in the EU. Imvanex is marketed as Jynneos in the US where it is authorised for the prevention of both monkeypox and smallpox.

Considering the limited availability of Imvanex, EMA’s Emergency Task Force (ETF) has recommended that Jynneos can be used to provide protection against monkeypox disease in the EU. The task force has given this advice to support national authorities who may decide, as a temporary measure, to import Jynneos from the US in view of the rising rates of infection across the EU.

Hydroxyethyl-starch solutions for infusion recommended for suspension from the market- update

EMA has updated the terms of this suspension to indicate that “If necessary for public health reasons, individual EU Member States may delay the suspension for no longer than 18 months and keep HES solutions on the market, subject to agreed risk minimisation methods.

[As I noted in the March edition of the Update the suspension was “An example of the regulators Risk Based decision making where risk of harm to patient v potential to save a life possibly appear to be in conflict. Obviously not an easy decision.” 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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