EDQM’S SUSANNE KEITEL ON PH. EUR. HOT TOPICS
In the last of four presentations at the opening plenary session of the international conference on the European Pharmacopoeia held in Tallinn, Estonia, EDQM Director Susanne Keitel reviewed EDQM’s role in the European regulatory framework, the ninth edition of Ph. Eur., and four “hot topics” now on the forefront of Ph. Eur. attention. The four topics, each of was discussed at a breakout workshop, are: ● setting pharmacopeial standards for biotherapeutic products ● the control of elemental impurities ● new technologies, and ● excipients, other components and international harmonization.
I have the feeling that I could do away with about half of my presentation, because the previous speakers have already touched upon the topics that I was planning to cover. But as one of my colleagues just said to me, repetition is always good for the learning effect.
I was planning to talk a little bit about the EDQM and the European regulatory framework, and you have already heard a lot about that. But I am definitely going to speak about the Ninth Edition of the European Pharmacopoeia — what is special and specific about it. And then I am going to finish by touching on current hot topics. The idea is to provide you with sort of an introduction or a teaser to the workshops in order to avoid your running away this afternoon and enjoying the sunshine outside and visiting the beautiful town of Tallinn. So I am trying to do my best to keep you here with us at the conference.
I have to start with a few words about the parent organization of the EDQM, the Council of Europe. It is the oldest pan-European organization, founded in 1949, which has as a goal the development of European common and democratic principles. It should not be confused with the European Union. It has 47 member countries, and it is headquartered in Strasbourg. The core values of the Council of Europe are the protection of human rights, pluralist democracy and the rule of law.
You can see on the right-hand side, first of all, a map which shows all the member states of the Council of Europe, and you can see that it extends far more to the east compared to the European Union. For example, the Russian Federation is one of the member states, Turkey, Ukraine, Azerbaijan….
And then you see on the top, the flag that was created in the ‘50s for the Council or Europe, which now-a-days is also used by the European Union, and also by the EMA. So every time you see this flag in the future you will ask yourself, is this indeed the European Union or is it not the Council of Europe?
Now the EDQM, our European Directorate for the Quality of Medicines & HealthCare, is a Directorate of the Council of Europe…based on the ‘Convention on the Elaboration of a European Pharmacopoeia,’ which was signed by eight ‘visionary’ countries, as [Moderator Jean-Louis Robert] has referred to them, in 1964. Our mission is to contribute to a basic human right, which is access to good quality medicines and healthcare…
Now we have heard already that a lot of things have moved forward in the last fifty years or so. The European Pharmacopoeia started in 1964 with eight visionary founding member states of the Council of Europe. Today, the European Pharmacopoeia and the EDQM have 38 signatory parties – that is 37 countries plus the European Union. And you see them depicted in green. You can also see 26 of the currently 28 observers in yellow, and you can see that they really come from all over the world and cover all continents. And marked in the pink, you can see two parties with whom we have a very special relationship. These are our sister pharmacopeias in Japan and the United States. And [Swissmedic’s Petra Dorr], I think, has already referred to the Pharmacopeial Discussion Group [PDG] – slow but steady – and we will come back to that.
With the signature of the Convention on the Elaboration of a European Pharmacopoeia, a country commits to making the standards of the European Pharmacopoeia legally binding on their territory. The last country that decided to accede was Ukraine in 2012. But I thought it would be worthwhile – and I think [Paul-Ehrlich-Institute President Klaus Cichutek] has already referred to it – to make a note about the special status of the European Pharmacopoeia in the European Union pharmaceutical legislation.
It is referred to in the pharmaceutical legislation and Directive 2001/83/EC, for example, in the annex. There it is clearly stated that with respect to the quality part – they are talking about marketing authorization applications – all monographs and general chapters of the European Pharmacopoeia are applicable. So the European Union pharmaceutical legislation makes the European Pharmacopoeia binding.
Only in the case when there is no text in the European Pharmacopoeia, reference can be made to a national pharmacopeia of a member state. So each member state may require observance of its own national pharmacopeia. And only if there is no monograph either in the European Pharmacopoeia or in any one of the member states pharmacopeias, reference can be made to a third country pharmacopeia.
What has to be submitted in a marketing authorization application is a bit more extensive – for example, as regards validation of the analytical procedures contained in the monograph. And this is stated in the legislation.
This is a topic that we have heard a lot about before the coffee break, and I am quite happy because basically I can restrict myself to showing this slide. I don’t have to explain to you again that there is a close collaboration between the European Union – the Commission, the lawmakers, and the European Medicines Agency – and the national authorities of all our member states, be they EU or not. If I talk about national authorities, I am really talking about licensing authorities and inspectorates – OMCLs, the control laboratories, but also national pharmacopeia authorities and us, the EDQM of the Council of Europe in Strasbourg.
And it has been said before, clearly the mission is to make best use of scarce resources to ensure complementarity and to avoid duplication. And clearly, as I said, [like] the European Medicines Agency in London, the EDQM could not do anything without the unwavering support of the member states and the national authorities.
Ninth Edition of European Pharmacopoeia Enough about the position of the EDQM and the European regulatory framework. We are now going to talk about the Ninth Edition of the European Pharmacopoeia.
I would like to start by talking a bit about the pharmacopeia. As you all know, the governing body is the European Pharmacopoeia Commission, which holds three sessions per year, so it meets three times, in Strasburg. It is composed of 38 delegations, the 37 member states plus the EU. And all delegations are entitled to submit up to three representatives.
What is unique about the European Pharmacopoeia Commission is that all technical decisions are taken by consensus. And you can imagine that this is not always the most easy task to achieve. So there is no voting. If there is one member state that does not agree, forget about it. But I think over the last 52 years or so, everybody on board has learned that it is compromising. It is give and take. So normally it works.
And the European Pharmacopoeia Commission is also very happy that quite a number of the current 28 observers regularly come to the sessions of the European Pharmacopoeia Commission to participate in its work.
This is the portfolio that the European Pharmacopoeia currently covers.
As you can see, more than 50% of the texts are still dedicated to…chemically defined substances. You can see that the next group of importance are herbals. Herbals are gaining more and more attention. Then you can see that basically the pharmacopeia covers a lot of different issues from dosage forms, radiopharmaceuticals, vaccines – be they human or veterinary – plastic materials, blood derivatives, antibiotics, medicinal gases, homeopathy and also biologicals – again, a topic which is getting more and more important.
I am quite proud to say that the European Pharmacopoeia really is a success story. It is a unique example of an efficient collaboration between member states – 37 member states who have decided to contribute their resources to a collaborative process, instead of trying to develop their own national standards.
And this is also imbedded in the rules of the European Pharmacopoeia: that as soon as there are two members states interested in one topic, it is brought to the attention of the European Pharmacopoeia Commission and normally added to its work program…. The member states can only develop an individual monograph if there is nobody else interested. And secondly, they have to notify the European Pharmacopoeia Commission.
The opportunities I believe are evident in saving our resources, and also that the outcome is always a harmonized text, which does not need any further harmonization.
The concrete outcome that we talked about with the European Pharmacopoeia 9th Edition are 2,329 monographs and 358 general texts which have been published in the 9th Edition.
I have mentioned the European Pharmacopoeia Commission – the governing body – is very important. But at least equally important are the numerous experts who participate in the elaboration or revision of the text of the European Pharmacopoeia.
Currently we count 58 active groups of experts in working parties. This is something that changes over time because new working parties are created as new topics arise or others are disbanded. They are supported by an additional 13, what I would like to call, dormant groups, which are still around in case there are, for example, questions from users to give advice.
The texts that I have referred to are all adopted by the European Pharmacopoeia Commission for publication, and then they become legally binding in all of the 37 European Pharmacopoeia member states and the European Union.
As we said already earlier today, they are applied in more than 100 countries worldwide. So clearly from the inception of the European Pharmacopoeia with a focus on what Europe needed to do, we have reached an era of globalization. And clearly the outreach of the European Pharmacopoeia goes far beyond Europe today. Ph. Eur. Network The European Pharmacoopeia network, the experts behind the success of the European Pharmacopoeia, are clearly an asset.
We have currently more than 700 experts in the different groups. We are very happy that they have a very balanced background: ● Approximately a third comes from health authorities – with the ministries and different competent authorities, pharmacopeia authorities, inspectorates. ● Approximately a third comes from industry. ● And the last third comes from universities or hospitals.
They are nominated by member states based on their specific expertise, and then they are appointed by the European Pharmacopoeia Commission.
These 700 experts are currently supported by about 60 experts from observers. As you can see, again, they come from all parts of the world.
As I already alluded to in my opening remarks, the European Pharmacopoeia Commission has taken a significant decision to open up nomination of experts to all countries around the world. So as of this year – and we are currently running the next cycle of nomination of experts – experts from all around the world can actively apply to contribute to the elaboration of the tenth edition of the European Pharmacopoeia.
This is the concrete outcome. You can also see this on the banner. The ninth edition published in the conventional paper format. There is an on-line version on the internet, on your computer, on your laptop or any other mobile device, and also still as a USB drive.
9th Edition Coverage
This is what the ninth edition covers: I am not going to repeat the numbers again, but I think it is quite interesting to look into what the figures stand for. We have 87% specific monographs in the European Pharmacopoeia, and 13% general text.
Now Klaus made a point about becoming quicker and the need to revise and adapt, etc. So I think it is quite interesting to look at the blue pie chart, where you will see that 5% of the text contained in the ninth edition is indeed absolutely new, 52% has been revised, and the remaining 43% are unchanged. So I hope, Klaus, that we can convince you that we are not sitting there and thinking that the pharmacopeia standards are cast in stone. We are very much aware that there is a constant need to follow developments and to revise and update.
In addition, the European Pharmacopoeia also includes about 2,600 descriptions of reagents.
Ph. Eur. Hot Topics Now I am going to move onto the current hot topics, and as I said, try to convince you not to run away this afternoon.
So what is this conference about? Well first of all, before saying that this is a really great place and we would really like to go there, we were so proud that we managed to publish the ninth edition. But we also felt an urgent need to engage with you, our stakeholders, because a lot of things are going on in various fields. We have identified four topics where we would really be happy to get your feedback in order to help us, the European Pharmacopoeia Commission, the experts, but also the secretariat, to find the way how to move on.
These are the four topics that I have already mentioned in my welcome remarks: ● pharmacopeial standards for biotherapeutic products ● thinking of Klaus again – new technologies and their potential impact of monographs ● control of elemental impurities, and also ● excipients and international harmonization.
Well of course you are aware that we do not only use these conferences to seek your feedback. We publish all the texts for public inquiry in Pharmeuropa. We organize dedicated hearings with industry and industry associations. We organize workshops dedicated to specific topics. We have organized similar international conferences – in Prague in 2010, and the last one in Strasbourg two years ago.
The intention is to share the outcome and the feedback of this conference, of these two days, with the European Pharmacopoeia Commission, with the idea to helping them fine-tune their three-year priorities from 2016 to 2019. And these are what I would like to call the Tallinn workshops. As you can see, we had the feeling that pharmacopeia standards for biotherapeutic products is such a hot topic, with so many different facets that deserve sufficient time, that we decided to dedicate two sessions to one topic. So there will be a first session on documentary standards, and the second session will be on material standards/reference standards.
For the other three workshops, we have decided to have a session that will then be repeated, which of course has the advantage that you will also have the possibility to not only attend one workshop.
Standards for Biotherapeutic Products I just said that standards for biotherapeutic products is a hot topic. When you discuss this, sometimes you have the feeling that this is a new topic – that biotherapeutic products are new for pharmacopeias. But looking back you will see that is not true at all.
In the 1970s, as you can see on the slide, the focus was on vaccines for human and veterinary use. So a lot of monographs, thirty individual monographs – for example, vaccines for human use – were published in the second volume of the first edition of the European Pharmacopoeia already in ‘71.
Vaccines for veterinary use: Again, seven individual monographs followed in the supplement to volume three. And in 1974, we also saw the publication of monographs on insulin preparations.
I am going to skip the 1980s – and I am sure that in the biotherapeutic workshop you will hear more about this – because the ‘80s were dedicated to blood products and substances extracted from animal tissues.
Looking into the ‘90s, products of recombinant DNA technology arrived – a change in the General Notices with the introduction of the production section, which nowadays is part of many monographs, but it was indeed elaborated with a focus on biotherapeutic products.
You see that in 1997 with the third edition, the General Notices included references to alternative methods and also compliance with European Pharmacopoeia monographs – what does it mean.
You can see that the European Pharmacopoeia Commission tried all the time to take into account the specifics of biotherapeutic products, and also the need for a certain flexibility. And you can also see a lot of individual monographs that were adopted over the time.
Now looking into this century, the first decade with the appearance of biosimilars, you can see that the EMA became very active in the field of developing specific guidelines on biosimilars. You can see that in 2005, the general monograph for monoclonal antibodies was adopted. You can see that there were more activities of EMA in specific guidelines for biosimilars. And it is important to highlight that in 2008, the P4 pilot phase was initiated to cover biotherapeutic products.
Just for those who are not that familiar with the workings of the European Pharmacopoeia Commission, basically there are two procedures: ● P1, which is what we call the multisource procedure, where you cover all the products which are on the market, and ● the P4 procedure, which is dedicated to substances that are still under patent or patent data protection, where it is a collaboration directly with the innovator and, of course, only if the innovator is interested.
In this decade, you can see that in 2011 the EDQM organized a workshop on the future of monographs in the field of biologicals. It was a closed workshop with regulators to hear more about their position, because we sometimes have the feeling that regulators were a little bit cautious and not so convinced about the added value of the pharmacopeia standards for biotherapeutic products. This was an important workshop, and it provided us with a lot of information and what we should do or could do, which was also in the interest of regulators.
You can see that, for example, this led to the addition of teriparatide to the P4 bio work program in 2012. You can see that in July 2014 the general notices were revised again to take account of the principles of PAT, real time release testing [RTR], the 3R’s [refine, reduce and replace] – very high on the agenda of the Council of Europe and the EDQM for a long time – consistency approach. And then you also see that at the last conference two years ago [there was] a dedicated workshop on biologicals.
Now, what is at stake and what is the idea for the workshop later today? Since 2012, three P4Bio monographs have been adopted — the last one was teriparatide in 2015. Two other monographs, on pegfilgrastim and etanercept, were published in Pharmeuropa for public consultation. The consultation period ended for NPAs in August this year.
Klaus has already made reference to an infliximab monograph. This first monograph on a specific monoclonal antibody is very close to publication in Pharmeuropa for public enquiry. That will happen in October. He referred to the methods that are provided in this monograph, which have undergone extensive verification with the contribution of the OMCLs.
The workshop this afternoon and tomorrow morning is dedicated on setting pharmacopeial standards for these products, because we know that there are some concerns on the industry side. There are some ideas and concerns on the side of regulators. So it is crucial for us to gather your feedback and to get your recommendations. I can only ask you to please get involved.
Impurities The second topic that I would like to raise is the one on impurities. Clearly control of impurities is something that the European Pharmacopoeia is very proud of. It clearly is a strength of the European Pharmacopoeia.
The Commission already decided in the early 2000s to fully embrace the principles of ICH Q3A, which led to the drafting of transparency lists at the end of monographs. But again, coming back to the need to stay updated: A transparency list needs to be updated as new routes of synthesis arise, as manufacturers modify routes of synthesis. So clearly input from users is needed to update when and where needed.
Another hot topic is the control of impurities in antibiotics. Those of you who have followed the adoption of a specific guideline by the Quality Working Party at EMA on control of impurities in antibiotics have seen that the requirements there are much more stringent compared to what has been traditionally done in European Pharmacopoeia monographs. So clearly this is a particular challenge for the respective working group of experts, and it will need the attention of the European Pharmacopoeia Commission in coming years.
The European Pharmacopoeia is also in the process of fine tuning the implementation strategy of the ICH M7 on the assessment and control of DNA-reactive impurities in pharmaceuticals. This is being discussed with the different relevant European Pharmacopoeia groups of experts.
Now the workshop today and tomorrow is focusing on the implementation strategy of the ICH Q3D guideline on elemental impurities. Clearly, what had been decided from the beginning was to align as closely as possible with regulators, and also with the timelines of regulators. But, as so often, there is more to the guideline and the implementation than meets the eye at first glance.
A topic that was identified as one which is a bit more tricky and which deserves specific discussion is for example, mined excipients. So clearly there is a need for your feedback.
There is also the intention to revise general monographs on substances for pharmaceutical use and on pharmaceutical preparations, as well as the two relevant chapters – the one which is also undergoing pharmacopeial harmonization with our sister pharmacopeias, JP and USP, on the how to, and then the one which currently contains the text of the previous EMA guideline on control of metal residues. These are proposed for adoption at the next session of the European Pharmacopoeia Commission in November. So if you have any concerns about them, use the opportunity and speak up during the workshop.
In order to allow the European Pharmacopoeia Commission to take an informed decision, this workshop is dedicated to the control of elemental impurities, and it would be great to have your feedback. Just to let you know, as already referred to, the Chapter 2.4.20 will, in any case, afterwards be discussed with our sister pharmacopeias to ensure that the three PDG pharmacopeias deliver what they have promised to ICH – namely to come up with harmonized methods.
New Technologies In the field of new technologies, again I can refer to Klaus’s presentation. It is important for the applicability of the requirements in the European Pharmacopoeia that the techniques commonly used in practice are robust…. Of course we know that there may be highly sophisticated and less commonly used techniques, which may be the method of choice when relevant quality parameters cannot be determined otherwise. So we need to follow what is going on in regards to [others].
What we do need to do is to further reflect on allowing techniques to become the new standard method once they are commonly used, and replace old standard methods. And one example is the replacement of HPLC by fast HPLC.
But we also need to assist those users who might not be that experienced or familiar with new methods. We need to establish guidance for new techniques. This is something that has been recently done, for example, in the field of chemometrics. So this is something that needs to be discussed and assessed.
Our idea is to collect feedback from you during this workshop, which we will, again, provide to the Commission at an upcoming session in order to have them determine the need to revise existing chapters and whether there is a need to develop new ones. Again, have a say and express your needs. Excipients, Other Components and International Harmonization Finally, the last workshop: Excipients, Other Components and International Harmonization. We will have an interesting presentation on a new project which is an elaboration of the general monograph on co-processed excipients. We will be really interested to know whether this draft monograph, which has been published for public consultation, matches your needs.
We will hear more about the revision of the water for injection monograph, which now allows the use of non- distillation techniques. The question to you is, is this the happy end, or is there more that you would like to happen?
You will hear an update on developments in the field of packaging materials, and about international harmonization. I can refer to Petra’s very comprehensive discussion. Of course, international harmonization is a key area of interest to many users and stakeholders – not only of the pharmacopeias, but also industry. As such, I would not limit it to pharmacopeial standards.
As you know, there are several initiatives going on: ● PDG, Pharmacopeia Discussion Group, as we heard ● good pharmacopeia practices – an initiative under the auspices of the WHO. You will hear more about it. And I think I can stop with the acronyms. Petra has already provided a sufficient number this morning.
So again, feedback from users will be gathered during the workshop and will be provided to the European Pharmacopoeia Commission at an upcoming session and, where relevant of course, it will also be shared with our sister pharmacopeias at the level of the PDG.
With that I would like thank you a lot for your attention, and we are very much looking forward to a lively discussion this afternoon and tomorrow morning and to receiving your feedback. Thanks a lot.