Tackling Challenges and Change Together

Setting public standards for medicinal products in Europe has come a long way over the past 50 years. The 1st Edition of the European Pharmacopoeia (Ph. Eur.), published in 1969, comprised a modest 120 texts. The 9th Edition of the Ph. Eur., published in July 2016 – and due to become legally binding in 37 European countries and the European Union as such on January 1, 2017 – contains some 2,300 monographs and more than 350 general texts.

But the numbers only tell part of the story. Collaboration has been the key from the very beginning. Today, there are 37 member states of the Ph. Eur. Convention and the EU, 28 observer states and organizations, and 700 or so experts in every field of the pharmaceutical sciences – all volunteers – who participate in more than 70 groups of experts and working parties. Each and every one of them makes an invaluable contribution to setting Europe’s legal and scientific benchmark for pharmacopeial standards.

This collaborative result, however, is not a linear process; rather, it is a dynamic, complex interaction of all parties involved.

In this article, I will focus on recent changes in the work of the Ph. Eur. Commission and the European Directorate for the Quality of Medicines & HealthCare (EDQM). The Ph. Eur. is published by the EDQM, which enables the development, supports the implementation and monitors the application of quality standards for safe medicines and their safe use. The activities of the EDQM include providing the scientific secretariat to the Ph. Eur. Commission, which is composed of delegations of the 38 signatory parties. The Ph. Eur. Commission is responsible for the development of new monographs and general texts, as well as the revision of existing texts. The EDQM also regularly organizes consultations, meetings, webinars and other events with stakeholders to ensure that the Ph. Eur. remains relevant to industry and its other users.

Given the daily impact of globalization on pharmaceutical activities in specific geographical zones, regulators and standard setters worldwide are actively seeking to exchange information and collaborate in areas where international harmonization of standards makes real sense. With this in mind, the Ph. Eur. Commission has made some changes recently that I think are very relevant and interesting for stakeholders.

Opening doors

In November 2015, the Ph. Eur. Commission decided to revise its working procedures to allow experts from outside of Europe to become further involved in its work. Traditionally, experts wanting to get involved with the Ph. Eur. had to be nominated by a member state. However, the reality of today’s pharmaceutical environment is that it is becoming increasingly globalized. To take just one example; more than 80 percent of the active pharmaceutical ingredients used in medicines for the European market today are produced in countries outside of Europe and the US. It is also no coincidence that the Ph. Eur. is recognized and used in more than 100 countries worldwide – and not only in the Ph. Eur. member states.

This decision to bring in experts from all over the world is a significant one for us, and I believe it will ensure that the Ph. Eur. is even more representative and encompassing of worldwide developments. Experts from non-Ph. Eur. member states and non-observers states can now be nominated for the Ph. Eur.’s groups of experts and working parties, which are crucial in the ongoing elaboration and revision of the methods and texts of the Ph. Eur.

In aiming to make it easier for important potential contributors to become involved, we have also removed the limitation of one member state expert in a group and simplified the process for nominating ad-hoc specialists to support the work of the Ph. Eur.

As a next step, the Ph. Eur. Commission recently launched a worldwide call for experts ahead of the next session in November, when all the members of the current groups of experts and working parties will face re-appointment (which happens every three years). At the moment, health authorities, industry and academia each provide approximately one-third of participants.

These recent changes have also influenced the structure and focus of the EDQM’s upcoming conference in Tallinn (Estonia) on September 27-28. To mark the publication of the 9th Edition of the Ph. Eur., the EDQM is organizing a major international conference: the European Pharmacopoeia: Tackling Future Challenges of the Quality of Medicines Together. The main focus of the conference will be workshops dedicated to four key topics: new technologies; the control of elemental impurities (i.e., the impact of the ICH Q3D Guideline); setting pharmacopeial standards for biotherapeutic products; and excipients, other components and international harmonization.

The four workshops are intended to provide a platform for the exchange of experience and opinions – and the feedback will help the Ph. Eur. Commission and EDQM to define their priorities across the board for the next three years. The chosen topics are reflected in the revisions and new additions to the 9th Edition of the Ph. Eur. In terms of new technologies; for example, the Ph. Eur. is the first pharmacopeia to include a general text on the application of chemometric methods to analytical data. However, I think that the workshops on the control of elemental impurities and on setting pharmacopeial standards for biotherapeutic products are particularly important.

Addressing elemental impurities

Preparations are in hand for the implementation of the ICH Q3D guideline on elemental impurities, which covers the evaluation of toxicity data for potential elemental impurities, a permitted daily exposure for each element of concern, and the development of controls to limit the inclusion of elemental impurities in finished drug products. The Ph. Eur. Commission has decided to reproduce, in the current general chapter ‘Metal catalyst or metal reagent residues’ (5.20), the principles set out in the ICH Q3D guideline. As a consequence, the current general method ‘Determination of metal catalyst and metal reagent residues’ (2.4.20), which describes the general approach for the determination of metal catalyst or metal reagent residues in substances for pharmaceutical use, will also be revised.

The Ph. Eur. Commission intends to introduce a cross-reference to revised general chapter 5.20 in the general monograph ‘Pharmaceutical preparations’ (2619), thus making application of the ICH Q3D guideline legally binding for all medicinal products within the scope of ICH Q3D. This revised general monograph is expected to be published in Ph. Eur. Supplement 9.3 on 1 July 2017; chapter 5.20 will become legally binding as of January 1, 2018.

A revised version of the general monograph ‘Substances for pharmaceutical use’ (2034) has also been published for public comment and has been revised to clarify how to handle substances used in pharmaceutical products outside the scope of the ICH Q3D guideline. It is also expected to be published in Ph. Eur. Supplement 9.3.

Already, the 9th Edition contains 760 individual monographs that have been revised to delete the reference to the general chapter Heavy metals (2.4.8). The revised monographs cover substances for human use only and for human and veterinary use, but not substances for veterinary use only.

The biotherapeutic discussion

I see the biotherapeutic product workshop as a great forum for stimulating, controversial and productive discussions. Following the approval of recombinant human insulin in 1982, which was the first biological derived from recombinant DNA technology, more than 200 biotherapeutics have received regulatory approval in Europe. Ph. Eur. quality standards have been elaborated for many of these first-generation biotherapeutics, such as peptide hormones, growth factors and interferons. Traditionally, these monographs have been elaborated using data submitted by several manufacturers of products authorized in Europe (this is known as the ‘multisource approach’).

Other first-generation biotherapeutics – such as interleukins, coagulation factors and monoclonal antibodies – have recently faced (or will face) patent expiry in the near future, which reinforces the need for public standards. This is also the case for second-generation biotherapeutics, a class of modern biological substances that have undergone engineering to alter their pharmacological activity. To make standards for this latter class of biotherapeutics available at the time of their patent expiry, we have developed an alternative mechanism for elaborating Ph. Eur. monographs, developed in close collaboration with single manufacturers (the so-called single source or “P4” approach). This alternative mechanism has been a pilot project since 2008 and will be completed at the end of 2016. In the June 2016 session, the Ph. Eur. Commission concluded that the work performed during the pilot project has successfully proven that it is possible to use this single source approach – and that it is extremely useful for elaborating public standards for complex biotherapeutic molecules, while at the same time providing flexibility in their requirements to allow for the future development of products. However, a number of stakeholders have their reservations against this approach so the Tallinn conference, especially this workshop, will provide a timely forum for exploring the shades of opinion on this very important question.

Discussions such as these are crucial for preparing for the future and maintaining the relevance of the Ph. Eur. in the ever-changing globalized pharmaceutical environment. By continuing to work together with experts from national and European authorities, universities, scientific institutes and industry, and by taking concrete steps to ensure the participation of experts from around the world, I believe that the Ph. Eur. is well-prepared for the future.

Susanne Keitel is Director of the EDQM.