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Updated: Feb 29

Review of Developments in GMP and the Regulation of Medicines May 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, USA and Australian regulatory authorities.

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



Medicines and Healthcare Regulatory Authority (MHRA)

  • Medical devices – extended acceptance of CE marked medical devices on the Great Britain market


  • Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG) 2022

  • New features further strengthen Priority Medicines scheme (PRIME)

  • Q&A on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - Scientific guideline

  • Single-arm trials as pivotal evidence for the authorisation of medicines in the EU

  • Management of ongoing clinical trials impacted by political conflicts, natural disasters or other major disruptions.

  • Human Medicines Highlights Issue 168

  • SME Office Newsletter

  • Q&A on the Statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU

  • CEP holders invited to comment on draft monographs published in Pharmeuropa 35.2

  • Public consultation on new general chapter on phage therapy active substances and medicinal products for human and veterinary use in Pharmeuropa 35.2

  • Outcome of the 175th session of the European Pharmacopoeia Commission.

  • Reference Standards



  • Notifying FDA of a discontinuance or interruption in manufacturing of finished products or active pharmaceutical ingredients

  • Assessing adhesion with transdermal and topical delivery systems for ANDAs

  • Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs

  • Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products



Australia

Therapeutic Goods Administration(TGA)

  • Dual labelled medicines begin transition to sole medicine ingredient names

  • First vaccine to protect older adults from respiratory syncytial virus (RSV) infection


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Medical devices – extended acceptance of CE marked medical devices on the Great Britain market

A statutory instrument has been laid in Parliament, which will enable an extended timeframe for acceptance of CE marked medical devices on the Great Britain market.

Subject to Parliamentary approval this will mean that CE marked medical devices will be accepted on the Great Britain market beyond the current deadline of 30 June 2023. This will support the ongoing, safe supply of medical devices to Great Britain and is designed to ease the transition.

MHRA are aiming for the revised framework to now apply from July 2025. In setting this timeline MHRA has taken on board feedback from external stakeholders, such as concerns about limited capacity of conformity assessment bodies.


Europe


European Medicines Agency (EMA)

Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group (GMP/GDP IWG) 2022

There was no annual report from 2018 to 2020 as a result of the EMA Business Continuity Plan (BCP) due to the effects of the UK withdrawal from the European Union. The BCP was extended in 2020 due to the COVID-19 public health emergency. The GMP/GDP IWG has met through 2022 virtually via remote meeting platforms, with resumption of in person meetings in November 2022.

The GMP/GDP IWG provides input and recommendations on all matters relating directly or indirectly to GMP & GDP.

[A good succinct summary of important topics. Also it is gratifying to see some return towards normality post Covid.MBH]

A further document covering developing the 3-year work plan (through to Dec 2023) for the Quality domain - Input from GMDP IWG is also available

New features further strengthen Priority Medicines scheme (PRIME)

EMA is introducing a number of new features to the PRIME scheme to strengthen its support for the development of medicines in areas of unmet medical need. The PRIME scheme enables earlier availability of life-changing medicines for patients.

The implementation of the new features follows a review which highlighted some opportunities for further strengthening the scheme.

  • To optimise the early scientific and regulatory support provided to promising medicines.

  • A roadmap for each PRIME development alongside a product development tracker will be established. Expedited scientific advice can now be provided specifically for PRIME developments in case of issues with a specific development programme that has already received comprehensive initial advice.

  • Submission readiness meetings, which will be held approximately one year ahead of the submission of a marketing authorisation application with developers of PRIME medicines. The scope of these meetings is to discuss the status of the development including the implementation of previous regulatory advice, and the resulting data package.

These initiatives aim to facilitate and accelerate the generation of robust and relevant evidence for the evaluation of a marketing authorisation application, which will give patients earlier access to transformative treatments that can make a real difference.

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).

Deadline for comments is 31 May 2023

Single-arm trials as pivotal evidence for the authorisation of medicines in the EU

EMA has opened a public consultation on a Reflection Paper that discusses key concepts for single-arm clinical trials that are submitted as pivotal evidence in support of marketing authorisation applications for medicines in the European Union (EU). This is the first guidance document by an international medicine regulator articulating the considerations and challenges associated with this type of clinical trials. Randomised clinical trials (RCTs) in which a new treatment is compared against a placebo or an existing standard of care are widely considered as the gold standard for generating evidence needed by regulatory authorities to assess the efficacy and safety of a new medicine. In RCTs, patients are randomly assigned to either the active treatment or the control arm. Usually, large numbers of patients are included for these trials to generate robust data on the efficacy of a treatment.

In certain areas such as rare diseases, including rare cancers, where target populations of new medicines are often very small, a proportion of marketing authorisation applications are submitted to EMA with clinical data from single-arm trials as pivotal evidence. Because there is no randomised comparator in a single-arm trial, all patients in the trial receive the experimental treatment and only the outcomes under the experimental treatment can be observed.

Stakeholders are invited to send their comments via an online form by midnight (CET) on 30 September 2023.

Management of ongoing clinical trials impacted by political conflicts, natural disasters or other major disruptions.

This points to consider document draws from the experience of past major disruptions in society, including the Covid-19 pandemic and the most recent developments of the Russo-Ukrainian War. These are varied in nature but may have similar, multiple consequences on clinical trials performed in the affected geographical areas. This document aims to help sponsors address the resulting challenges and mitigate risks to the rights, safety, dignity, and well-being of trial participants — a particularly vulnerable population — and to the scientific value of the clinical trials.

Human Medicines Highlights Issue 168

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 EMA. 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.

SME Office Newsletter

Issue #58 is now available

Q&A on the Statement on the scientific rationale supporting interchangeability of biosimilar medicines in the EU

EMA has issued Revision 1 of this Q&A.

The European Directorate for the Quality of Medicines and HealthCare (EDQM)

CEP holders invited to comment on draft monographs published in Pharmeuropa 35.2

Holders of Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) are requested to consult the list of substances for which draft revised monographs of the European Pharmacopoeia (Ph. Eur.) have been published in Pharmeuropa 35.2. Although these draft monographs are published for public consultation only at this stage and are therefore not official standards, they will, once adopted by the European Pharmacopoeia Commission, become legally binding standards for the substances concerned.

Public consultation on new general chapter on phage therapy active substances and medicinal products for human and veterinary use in Pharmeuropa 35.2

Phage therapy – the use of naturally occurring bacterial viruses (bacteriophages or phages) to treat bacterial infections – was first described in the early 20th century, but only remained in active use in a few countries. In recent years, however, phage therapy has regained the interest of physicians, researchers and industry as an attractive alternative to antibiotic treatment, particularly in the face of rising levels of antimicrobial resistance, increasingly frequent disruptions in antibiotic supply and an unmet demand for new antibiotics.

Addressing the quality of phage therapy has therefore been identified as a significant ongoing project for the EPC in the field of biologicals, and fulfilling the increasing expectations of users and being prepared for the future developments in this fast-moving field are amongst the European Pharmacopoeia Commission (EPC)’s priorities for 2023-2025.

Elaborated by the Bacteriophages Working Party (BACT WP) in response to these needs, the draft general chapter has now been published in Pharmeuropa 35.2, where it will remain open for public consultation from April until the end of June 2023.

Outcome of the 175th session of the European Pharmacopoeia Commission.

The 84 texts adopted by the EPC at this session will be published in European Pharmacopoeia (Ph. Eur.) Supplement 11.4 (October 2023), with an implementation date of 1 April 2024.

These 84 texts included 12 new monographs and 1 new general chapter

The EPC also adopted revised versions of 71 texts.

Reference Standards

EDQM announces the release of 20 replacement batches for Ph. Eur. reference standards.


United States of America

The US Food and Drug Administration (USFDA)

Notifying FDA of a discontinuance or interruption in manufacturing of finished products or active pharmaceutical ingredients

FDA is announcing the availability of a draft guidance for industry entitled “Notification of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act.” The draft guidance is intended to assist applicants and manufacturers in providing FDA with timely, informative notifications about changes in the production of certain finished drugs and biological products as well as certain active pharmaceutical ingredients (API) that may, in turn, help the Agency in its efforts to prevent or mitigate shortages. The draft guidance also explains how FDA communicates information about products in shortage to the public.

Assessing adhesion with transdermal and topical delivery systems for ANDAs

This draft guidance (Revision 2) revises the Revision 1 draft guidance of the same name, which was announced in the Federal Register on October 10, 2018. This revised draft guidance provides recommendations for the design and conduct of studies evaluating the adhesion performance of a transdermal or topical delivery system (collectively referred to as TDS). Depending on the objectives of a generic TDS product development program, applicants may choose to evaluate TDS adhesion in studies performed to evaluate TDS adhesion only, or in studies performed with a combined purpose (e.g., for the simultaneous evaluation of adhesion and bioequivalence (BE) with pharmacokinetic (PK) endpoints). The recommendations in this revised draft guidance relate to studies submitted in support of an abbreviated new drug application (ANDA).

Submit Comments by 12 June2023

Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs

This revised draft guidance provides recommendations for the design and conduct of studies to evaluate the in vivo skin irritation and sensitization (I/S) potential of a proposed transdermal or topical delivery system (collectively referred to as TDS). The recommendations in this revised draft guidance relate to studies submitted in support of an abbreviated new drug application (ANDA). The revised draft guidance is intended to clarify FDA’s recommendations and expectations related to in vivo skin I/S studies. This guidance revises the October 2018 draft guidance

Submit Comments by 12 June2023

Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products

This final guidance document replaces the draft dated February 22, 2019 and provides guidance to assist sponsors in the clinical development of nicotine replacement therapy (NRT) drug products, including but not limited to those intended for smoking cessation and related chronic indications.


International

Australia

Therapeutic Goods Administration(TGA)

Dual labelled medicines begin transition to sole medicine ingredient names

Currently some medicine ingredient names must be dual labelled. This means labels display both the old and new ingredient name. This was to allow people to become familiar with the new names. TGA chose the new names because they are recognised internationally. The dual labelling period for most dual labelled names will end on 30 April 2023. Medicine sponsors have 3 years to update labels to show only the new name for these ingredients. For some ingredient names dual labelling will continue for longer.


Products


First vaccine to protect older adults from respiratory syncytial virus (RSV) infection

EMA has recommended a marketing authorisation in the EU for Arexvy (recombinant, adjuvanted), the first vaccine for active immunisation to protect adults aged 60 years and older against lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV).

RSV can be serious in vulnerable people, including older adults and those with lung or heart disease and diabetes. In Europe, RSV causes an estimated 250,000 hospitalisations and 17,000 in-hospital deaths every year in people aged 65 years and older.

Arexvy contains an engineered version of the RSV fusion surface glycoprotein. This protein is essential for RSV to infect the body and is also the main target of the antibodies generated to fight the infection. When a person is given the vaccine, their immune system generates specific antibodies and T cells that help prevent RSV infection.

Arexvy was evaluated under EMA's accelerated mechanism because prevention of RSV infection in the elderly population is considered to be of major public health interest.

The opinion by EMA’s committee for human medicines (CHMP) is based on data from a randomised, placebo-controlled trial in 25,000 adults in 17 countries. The study is still ongoing and will be used to evaluate the efficacy of a single dose of Arexvy over multiple seasons and the need for re-vaccination, and to monitor its safety profile.



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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