Review of Developments in GMP and the Regulation of Medicines February 2020


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Vol 25-1B February-2020
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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 EU and USA regulatory authorities.


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


Europe

  • UK withdrawal from the EU on 31 January 2020

  • European authorities working to avoid shortages of medicines due to Brexit – updated Q&A

  • Ten recommendations to unlock the potential of big data for public health in the EU

  • Reflection paper on Good Manufacturing Practice and Marketing Authorisation Holders

  • Electronic product information for human medicines in the EU:key principles

  • Court of Justice upholds EMA’s approach to transparency

  • Substances considered as not falling within the scope of Regulation (EC) No. 470/20091, with regard to residues of veterinary medicinal products in foodstuffs of animal origin

  • Q&A on impact of EU-USA MRA on marketing authorisation applications and relevant variations

  • EDQM launches new Pharmeuropa website


USA

  • CMC information for human gene therapy INDs

  • FDA Continues Strong Support of Innovation in Development of Gene Therapy Products

  • Applications Affected by the Reorganization of the Office of New Drugs


Products

  • First oral GLP-1 treatment for type 2 diabetes

Conferences

  • MHRA Laboratories Practice Symposium

  • PHSS Aseptic Processing Syndicate Workshops


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EMA

UK withdrawal from the EU on 31 January 2020

The United Kingdom formally left the European Union on 31 January 2020 and became a third country to the EU. On 1 February 2020 a transition period started which is due to end on 31 December 2020. During the transition period, EU pharmaceutical law as laid out in the ‘Acquis Communautaire’ will continue to be applicable to the UK, meaning that pharmaceutical companies can continue to carry out activities in the UK until the end of the year. Companies have until 31 December 2020 to make the necessary changes to ensure that their authorised medicines comply with EU law and can remain on the EU market. Marketing authorisation holders/applicants can still be established in the UK and Qualified Persons for Pharmacovigilance (QPPVs) and pharmacovigilance system master files (PSMFs), as well as quality control testing sites, can still be based in the UK until the end of 2020.

As of 1 February 2020, no one who represents the UK, or is appointed or nominated by the UK can participate in meetings of EMA’s scientific committees, working parties or the Agency’s Management Board.

Updated Brexit-related guidance for companies has also been published.


European authorities working to avoid shortages of medicines due to Brexit – updated Q&A

The United Kingdom formally left the European Union on 31 January 2020 and became a third country to the EU. On 1 February 2020, a transition period started which is due to end on 31 December 2020. The relationship between the UK and the EU after this date is currently unknown and will be determined by future negotiations. During the transition period, European Union law in its entirety will continue to apply to the UK, meaning that pharmaceutical companies can continue to carry out activities in the UK as before until the end of the transition period. However, all interested parties should be mindful of legal repercussions when the transition period ends. To ensure that medicines can continue to be supplied in the EU after this period, companies carrying out certain activities in the UK will need to make changes to comply with EU law.


Ten recommendations to unlock the potential of big data for public health in the EU

The joint Big Data Task Force of EMA and the Heads of Medicines Agencies (HMA) proposes ten priority actions for the European Medicines regulatory network to evolve its approach to data use and evidence generation, in order to make best use of big data to support innovation and public health.

Big Data are extremely large, rapidly accumulating datasets captured across multiple settings and devices, for example through wearable devices, electronic health records, clinical trials or spontaneous adverse reaction reports. Coupled to rapidly developing technology, big data can complement the evidence from clinical trials and fill knowledge gaps on a medicine, and help to better characterise diseases, treatments and the performance of medicines in individual healthcare systems. The rapidly changing data landscape forces regulators to evolve and change the way they access, manage and analyse data and to keep pace with the rapid advances in science and technology.


Reflection paper on Good Manufacturing Practice and Marketing Authorisation Holders

This Reflection Paper is focussed on the GMP-related responsibilities that apply to Marketing Authorisation Holder (MAH) companies. While it is recognised that many MAH companies are not directly engaged in the manufacture of medicinal products themselves, the current European Commission (EC) guide to GMP (hereafter referred to as the ‘GMP guide’) refers, in several places, to MAHs and their responsibilities in relation to GMP. In general, these responsibilities relate to outsourcing and technical agreements, that require the MAH to perform certain specific tasks (e.g. evaluating the results of product quality reviews, agreeing irradiation cycles with manufacturers, etc.). These responsibilities are spread over the various chapters and annexes of the GMP guide, and are quite numerous. This Reflection Paper seeks to provide clarity as to what the various responsibilities are and what they mean for MAHs at a practical level.

In addition to the MAH responsibilities in the GMP guide, this paper also addresses the various legislative provisions (i.e. in European Directives and in other guidelines) which relate to GMP and which concern MAHs. Some of the responsibilities stated in the legislation (e.g. in Directives 2001/83/EC and 2001/82/EC) and in applicable guidelines are written in a way that they apply to marketing authorisation applicants, and they are included in this Reflection Paper because those provisions also convey responsibilities upon marketing authorisation holders in the post-authorisation phase. It should be noted that, as indicated in Annex 16 of the GMP guide, the ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the MAH. It is also important to note that, while certain activities of an MAH may be delegated to a manufacturer or other party, the MAH retains the responsibilities which are outlined in this paper. The GMP guide also does not provide for reduced MAH responsibilities (or for the delegation of responsibilities) in situations where the MAH and the manufacturer belong to the same overall group of companies but where the two companies are different legal entities. There is no difference in the responsibilities that apply to the MAH in this situation relative to when the MAH and the manufacturer are from separate and unrelated companies. It is recognised that, while MAHs have a significant role in facilitating GMP and MA compliance, their responsibilities in this area can, in some cases, be difficult to comprehend when reading the GMP guide or the applicable legislation. Notwithstanding this, such responsibilities are there and may be inferred. This Reflection Paper seeks to provide clarity on these.

The deadline for comments is 17 April 2020.

[Reflection papers have in the past covered fairly contentious issues where practices across Member States may vary. As such they can bring about considerable debate and differences of opinion between interested parties MH]


Electronic product information (ePI) for human medicines in the EU:key principles

This document is a joint EMA–HMA–EC collaboration arising from a workshop held at EMA on 28 November 2018 that brought together patients / consumers, Health Care Professionals, the pharmaceutical industry, academia, not-for-profit organisations and regulators to discuss stakeholder needs and concerns, give an overview of the main ePI initiatives ongoing in the EU and decide how to move forward with a common approach. The outcome of the workshop was a draft proposal for ‘key principles’ for ePI. These key principles were the subject of a 6-month public consultation (from January 31, 2019 until July 31, 2019). Following the consideration of submissions received during the public consultation, the key principles were updated. They now represent EMA-HMA-EC guidance on ePI and form the basis of follow-up implementation plans for ePI.


Court of Justice upholds EMA’s approach to transparency

Two appellate judgments by the Court of Justice that confirmed, in clear and unambiguous terms, the right of citizens for access to clinical study and toxicology reports submitted to EMA for the purpose of the granting of a marketing authorisation for human and veterinary medicinal products. The Court of Justice reiterated the principle of the widest possible public access to documents held by Union institutions, bodies, offices and agencies. An exception to that principle may be applied for the protection of commercial interests only if it is proven by the marketing authorisation holder/applicant that the disclosure of documents would pose the risk of a concrete harm to the commercial interests of the persons concerned. The Court of Justice agreed with EMA that such harm was not established in respect of the disclosure of the clinical study and toxicology reports at stake. The judges confirmed that transparency must be the rule and exceptions must be applied and construed narrowly.


Substances considered as not falling within the scope of Regulation (EC) No. 470/20091, with regard to residues of veterinary medicinal products in foodstuffs of animal origin

Since the implementation of Council Regulation (EEC) No. 2377/90, the CVMP has deliberated on many substances (including excipients, adjuvants and preservatives) to be used in veterinary medicinal products intended for food producing species, and regularly receives requests (either scientific advice or ad hoc requests) to consider whether such substances fall within the scope of the MRL regulation. The substances for which the CVMP has concluded that no MRL evaluation is required are listed in the CVMP publication “Substances considered as not falling within the scope of Regulation (EEC) No. 2377/90” (EMEA/CVMP/046-00), also often referred to as the ‘out of scope list’. The list also includes a small number of compounds that do not fall within the categories of excipients, adjuvants or preservatives but are natural substances essential for life or are biologically active constituents. Due to the nature of these specific compounds the CVMP considered that an evaluation for the establishment of maximum residue limits would not be appropriate. Following the implementation of Regulation (EC) No. 470/2009 there was a need to update the background information and legal references included in the document containing the ‘out of scope list’. This document performs that function and supersedes the CVMP publication Substances considered as not falling within the scope of Council Regulation (EEC) No. 2377/90. The list presented on the following pages includes all the substances included in the superseded document. It should be noted that this list of substances is in no way exhaustive and includes only substances for which requests in this respect were made to CVMP by a company or a national authority


Q&A on impact of EU-USA MRA on marketing authorisation applications and relevant variations

Q&A 1 relating to ‘How does the EU-USA Mutual Recognition Agreement (MRA) affect marketing authorisation applications or variations’ has been revised.


EDQM

EDQM launches new Pharmeuropa website

EDQM has developed a new Pharmeuropa website, which went live on 23 January 2020.

The new website has been redesigned and now has more features that are expected to improve the user experience. For example:

  • single sign-on with other EDQM websites using the same authentication database, including Ph. Eur. online and PaedForm;

  • improved navigation using standard web browser functionality;

  • tablet and smartphone friendly;

  • improved search query management;

  • a notification tool enabling users to set alerts for important information for their business, based on monograph numbers or Ph. Eur. groups of experts.

All users will have to register for access, even those who had access to the previous site.


United States of America

The US Food and Drug Administration (USFDA)

CMC information for human gene therapy INDs

This guidance finalizes the draft guidance of the same title dated July 2018 and supersedes the document entitled “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),” dated April 2008 (April 2008 guidance). The field of gene therapy has progressed rapidly since the previous April 2008 guidance. Therefore, FDA is updating that guidance to provide current FDA recommendations regarding the CMC content of a gene therapy IND. This guidance is organized to follow the structure of the FDA guidance on the Common Technical Document (CTD).

The CMC information submitted in an IND describes the sponsor’s commitment to perform manufacturing and testing of the investigational product as stated. FDA acknowledges that manufacturing changes may be necessary as product development proceeds, and information amendments should be submitted to supplement the initial information submitted for the CMC processes. The CMC information submitted in the original IND for an early phase study may be limited, and therefore, the effect of manufacturing changes, even minor changes, on product safety and quality may not be sufficiently understood. Thus, if a manufacturing change could affect product safety, identity, quality, purity, potency, or stability, applicants should submit the manufacturing change for FDA review prior to implementation.


FDA Continues Strong Support of Innovation in Development of Gene Therapy Products

This is a pivotal time in the field of gene therapy as the FDA continues its efforts to support innovators developing new medical products for Americans and others around the world. To date, the FDA has approved four gene therapy products, which insert new genetic material into a patient’s cells. The agency anticipates many more approvals in the coming years, as evidenced by the more than 900 investigational new drug (IND) applications for ongoing clinical studies in this area. The FDA believes this will provide patients and providers with increased therapeutic choices.

In that spirit, today, the FDA is announcing the release of a number of important policies: six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance, ‘Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations’.


Applications Affected by the Reorganization of the Office of New Drugs

The approved restructuring of the Office of New Drugs (OND) creates offices that align interrelated disease areas, and divisions with clearer and more focused areas of expertise. As a result, the names of OND’s offices and divisions have changed. If there is a change in signatory, or point of contact for applications currently under review, then sponsors will be notified. However, at the start of each phase, FDA encourages sponsors to search within the provided Excel file for applications currently under review that may be affected by the reorganization.


Products

First oral GLP-1 treatment for type 2 diabetes

EMA’s human medicines committee (CHMP) has recommended granting a marketing authorization in the European Union (EU) for Rybelsus (semaglutide) for the treatment of adults with insufficiently controlled type 2 diabetes to improve glycaemic control as an adjunct to diet and exercise. It is the first glucagon-like peptide (GLP-1) receptor agonist treatment - a class of non-insulin medicines for people with type 2 diabetes - developed for oral use, providing patients with another option to treat the disease without injections. The active substance in Rybelsus, semaglutide, acts in the same way as the incretin hormone GLP1: it reduces blood glucose by stimulating pancreatic secretion of insulin and lowering the secretion of glucagon (a hormone that works to raise blood sugar concentration) when blood sugar is high. The opinion adopted by the CHMP is an intermediary step on Rybelsus’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation.


Conferences

MHRA Laboratories Practice Symposium

Registrations are open to both commercial and non-commercial audiences, for this 12 Feb 2020 symposium. MHRA’s resident experts will analyse and converse on in-depth presentations around the theme of 'fit for intended use', in the context of regulated work across GLP, GCP and GMPQC laboratories.


PHSS Aseptic Processing Syndicate Workshops

Registration is open for these PHSS workshops to be held at the Marriott Worsley Park Manchester UK on 1-2 April 2020.

See the PHSS website for details.


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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