The European Pharmacopoeia and certificates of suitability (CEP)

on behalf of de d’Yquem I’d like to thank the organizers for giving us the occasion to present our activities the European Directorate for the quality of medicines in health care is actually based in Strasbourg accounts of Europe and it’s based his existence is based upon the convention that was drawn up by the Council of Europe 50 years ago to elaborate a European pharmacopoeia I think it’s a fair question why is the Council of Europe doing this what was the rationale behind it there were different reasons but this basic understanding is that it’s a basic human right is access to good quality medicines and health care it is considered that by pooling resources or within the different member states we can elaborate one common compulsory standard and this is a means of protecting public health where elaborate these monographs on the basis of what has already been demonstrated to be safe and I think it’s important to also point out the fact that because this is elaborated by the Council of Europe we are dealing with a larger Europe than the 27 member states of the European Union we have 37 Member States the European Union is also a member and so the text which is adopted by the Commission at European pharmacopoeia becomes mandatory in the same at the same date in 37 Member States and it’s legally binding and it’s it’s legally binding for raw materials preparations dosage forms etc and we’ll see a little bit of this in the next few minutes fifty years after work began it is over 2,200 monographs and different texts these go from active substances excipient radio pharmaceuticals vaccines I think it’s probably the moment for me to do a little bit advertised and we are going to be celebrating our fifty years by a conference in October Adobe plenary sessions and workshops you may want to to use our website and I think it’s also worthwhile knowing that if you have questions about this presentation we do offer a helpdesk facility where you can submit questions I’m going to move on to something which might seem obvious to a lot of people but as someone who used to respond to questions submitted on our helpdesk it’s clear that the general notices you do need to spend a little bit of time at reading to general notices and it sort of explains how to read how to interpret the different documents which are contained in the European pharmacopoeia so we do consider that it’s essential reading I said to the monograph stat the texts which are adopted they’re mandatory the European pharmacopoeia is also it does recognize that there can be a need for flexibility and it’s recognized that you can use alternative methods you don’t necessarily have to use the method which is described in the monograph you are free to use another method obviously there’s a condition to this that you get the same pass/fail result as if you were using the official method and you also have to demonstrate their suitability you have to validate this method and approval of the use of that alternative method it’s normally an alternative method it lays with the competent authority there is also flexibility in the sense that the monograph that the pharmacopoeia recognizes that you don’t actually have to carry out all of the tests of the of the monograph to be reassured that that material is suitable and is or pharmacopoeia quality you don’t have to carry out all the tests there’s different situations that may arise where you’re not going to want to carry out all of the tests you may be doing parametric release you may be using some of the elements of quality by design as strategies to avoid end product testing approval for this approach layers once again with the competent authority but it’s not something which is excluded by the European

pharmacopoeia so the monograph the mandatory if you are using a substance for thumb for for pharmaceutical use you have to demonstrate compliance the general notices makes it clear that there’s parts of the monograph which are mandatory and in there’s other parts which are for information it’s also made clear that when we’re dealing with raw materials or ingredients to manufacture a medicinal product that compliance is expected until the time of their use and for preparations they’re expected to comply during the validity of their storage the issue of in use compliance is not addressed this is something which is addressed by the competent authorities so any substance of pharmaceutical use should be complying with the monograph ingredients excipient s– solvents or buffers which may be used to make up the final formulation should be complying with the monograph where they exist it’s also made clear in the general notices that the test methods have been validated this means that on if on the basis of a consideration of the manufacturing route you would only expect to be finding those impurities which are listed in the monograph then that monograph method is considered suitable to control for those for that substance the method has been validated for those impurities you do not have to revalidate the official method obviously if you have additional impurities it’s then your responsibility to demonstrate whether the method is suitable or not there is an issue dealing with with the actual suitability of the method there are system suitability requirements and is also GMP requirements you need to respect these requirements but you don’t need to validate the method for any impurity which is listed in a transparency statement of the monograph there’s general chapters which have been introduced for editorial convenience there are standard methods of often they can give information and these don’t actually become mandatory until they’re referred to in a specific individual monograph in addition to the analytical methods there’s other types of general chapters a particularly important one has been mentioned dealing with the control of impurities and this this should be applied to any active substance whether or not there is an individual monograph in the European pharmacopoeia if there is no monograph for your active in the European pharmacopoeia you still need to be taken into consideration and showing conformity to this chapter another particularly important chapter deals with minimizing the risk of transmitting spongiform encephalopathy agents of our medicinal products this was introduced about 15 years ago now and this is legally binding the European pharmacopoeia has been working for the last nearly 20 years in an informal pharmacopoeia discussion group with the USP and Japanese pharmacopoeia w-h-o is an observer and the goal the aim of this of this work is to arrive at an interchangeable method which is to say that if you are using a method from the Japanese or the USP pharmacopoeia and it has been recognized as harmonized you can use it and you will find information on this procedure on the links there are general monographs which deal with classes of substances or on dosage forms they apply to all products except where it’s made clear that they do not apply but it’s something which is made plural agenda notices that there’s no cross-reference in an individual specific monograph it’s your responsibility to check whether it is a general monograph which applies to you there are particular reasons why this is done and it also makes it clear that you do need to know how to read a specific individual monograph the individual monograph for paracetamol on its own is insufficient you need to be able to read it taken into consideration any applicable general monograph the classes of the substances that they might be categorized according to how they’re obtained a product of fermentation it could be that they’re

classified according to their origin herbal origin or a vegetable fattier oil or it could be dealing with risk factors which are to be encountered during their manufacture if you’re using material which is at risk of transmitting a TSA agent for example and they deal with particular issues which can’t necessarily be it be dealt with in each individual monograph we get asked often which takes priority a general monograph for an individual monograph and as I hope you’ve understood you need to be reading both together they’re complementary there may be some exceptions but the times when you could just take the monograph for paracetamol and read that on its own have long gone you need to be taken together and they are often complementary substances of pharmaceutical use is a particularly important general monograph and it applies to any substance of pharmaceutical use irregardless of whether there’s a individual monograph the special needs situation is recognized you would need to be doing a particular risk analysis as to just how far you go and demonstrate in conformity to the requirements of of general monograph if you are manufacturing something for special needs which is to say outside of a marketing authorization pharmaceutical preparations it’s the source of standards which are to be applied but it doesn’t tell you how to manufacture two different types of medicinal products since there’s guidance which is else well and pharmaceutical preparations does not cover investigational medicinal products other a competent authority may invoke some elements of this general monograph when evaluating something for an investigational medicinal product the general monographs on dosage forms they’re applicable if if you are manufacturing a tablet you need to take into consideration the guidance in the dosage form for a tablet and it may well be that that monograph is insufficient you may need additional tests and these are to be approved by the competent authority all right I’ll now move on to my particular experience to certification procedure certification we we deliver different types of certificates of suitability it may be that you’re applying for a chemical or a horrible certificate of suitability which will reference a specific individual monograph or it may be that you’re applying for what we consider to be a TSE certificate because during manufacture of that substance you use material which is liable to be contaminated by THC agents so there’s two types there’s two basic types of a certificate a certificate when it’s been issued by us is accepted in the 37 Member States as well as the EU but there’s also countries throughout the world who have decided to start accepting certificates of suitability often these countries their observers did the European pharmacopoeias work and for the last six years we’ve had a memorandum of understanding with Canada and if you were to take the time to look at the list of Assessors who carry out the evaluation work you’ll see that there are Assessors from Canada who participate in evaluation in inner-workings transport but certificates they’re accepted by other countries it’s sort of one of my regrets in many ways that we don’t actually track in any sort of systematic way who’s accepting certificates we often discover who’s accepting a certificate of suitability through feedback from manufacturers but we know that Australia Singapore and South Africa they are accepting certificates of suitability we’re not involved if these countries have decided to do so we’re not involved and you would need to be checking with the local authority to know just what conditions need to be respected the certification procedure is 20 years old and it was about ten years ago that its existence was officially recognized in European Union law now it’s made clear in in directive 2003 63 that where a certificate of suitability has been issued for a substance this can replace the relevant parts of the CTD module and this was a big step forward for us this was a legal recognition of the work that we were doing certification provides a centralized evaluation as to whether the actual individual monograph is you dealing with a chemical application is

suitable to control the quality of your substance it’s considered that it can save time and resources instead of submitting an active substance master file to the different Member States you can according to European law use that certificate of suitability to replace parts of the module at the same time it was recognised that the evaluation to carry out the granting of a certificate of suitability could allow us to revise to improve the quality of the monographs of the European pharmacopoeia it’s a strange situation in many ways but it’s a fact of life the legal text the monograph can be deficient it may not be suitable to control the quality of your substance because you are manufacturing it in a way that wasn’t taken into consideration when a monograph was elaborated and so it’s the way during the evaluation process for a step it’s a way for us to feed information with the applicants consent back into the revision process to allow us to improve the monograph and the application is submitted directly to Strasbourg you don’t submit it to a national licensing authority you submit a documentation to us the year there’s a document which has been published it’s adopted by the Public Health Committee of the Council of Europe and it describes how to proceed it works I think it’s fair to point out the scope of the procedure they needs to be if you’re going to be making an application for an active or for an excipient we need to have a monograph in the European pharmacopoeia if there is no monograph we cannot accept an application however if in fact you want to be applying for a Tec certificate of suitability we will carry out that evaluation with regard to the TSE general monograph so in that particular situation that doesn’t have to be a specific monograph if to get that active or the excipient you are using material at risk of transmitting THC agents you can apply for a TSE certificate that is done and only done with regard to the TSE risk and the procedure is opened for a manufacturer regardless of their geographical origin I think it’s also worthwhile to point out that there’s certain categories of substances or products which are out of the scope as I said you need to have a monograph if you’re going to be applying for a chemical certificate biological substances substances which are extracted they’re out of the scope we’ve published we’ve made clarification on this there were we were accepting applications until about five years ago those certificates will continue to live their life so if you go consult in the list of certificates yes we have issued certificates for heparin these were these were applications made before we made a change in policy if you want to apply for a chemical certificate for heparin in 2014 the answer is no and the reasons why you’ll find in this document human tissue derivatives blood derivatives these are out of the scope mixtures of api’s with excipient they’re out of the scope unless it’s specifically recognized in a spit in an individual monograph that you make coat to substance this isn’t case-by-case and I would encourage you to contact us for clarification in advance the substance which you want to apply for a certificate of suitability that has to respect a definition section of the monograph and finished products are also out of the scope if you want to apply we’ve we’ve got a lot of documentation I think at the end of the day the fees are particularly interesting or we pay you need to pay three thousand euros for for a certificate dealing with a substance whether it’s chemical TS or horrible product there’s a possibility to apply for a sterile grade material oh this is an option you can have sterile mentioned in a subtitle there’s extra fees and if we actually have to carry out more than one type of evaluation which is to say you concerned by the tsa general monograph but you’re also manufacturing something for which there’s an individual monograph there’s extra fees the dossiers should be in English or French since we have two official languages in accounts of Europe I would encourage you to submit in English is what I can say but if you wish to submit in French you are free to do so just a brief explanation as to what we do we validate any application we will check

that we can actually handle that application so we will be doing validation it will go through an evaluation procedure where we have two Assessors who are evaluate the documentation if that documentation is incomplete we issue one request for additional information at issue is starting with is complicated distance um in some way we try and respect strictly the resolution we issue one request for additional information and after that hopefully we will issue the certificate of suitability or exceptionally we will have to refuse the application as I said the evaluation can also lead us to realize that the monograph is deficient so we can ask for a revision of that monograph once the certificate has been issued it then needs to be maintained up to date there’s a life cycle management I’m not going to go into that today but it is something that needs to be borne in mind variations need to be declared and accepted so what is this certificate of suitability mean it means for a chemical certificate that the quality of the substance is suitably controlled by that legal text by the European [ __ ] appear text and if that monograph is deficient additional tests will also be mentioned on that certificate so that it’s made clear what is needed to allow full and proper testing of that substance at ease the certificate will certify that the substance complies with the EMEA note for guidance which is the general monograph but it doesn’t necessarily mean that the quality of the substance is suitably controlled by any specific monograph that could exist and it’s important to realize that the certificate of suitability does not replace a certificate of analysis and it is not a GMP certificate although reference to GMP is mentioned on it we have for the last 14 years been inspecting manufacturers we are given a mandate by the European Union to carry out inspections we actually introduced a long time ago nearly sixteen years ago the requirement for confirmation that manufacturer is according to GMP it took us a couple of years to get to the stage where we can actually go verify that by an inspection and during the inspection we will check compliance with the information that was given in an application file is what is being done on-site actually what was described to us in the application file and it will also take into account the relevant GMP part 2 or if we’re dealing with a sterile grade material where sterile is actually mentioned on a certificate with the annex one and actions are taken immediately after the inspection if there’s major critical deficiencies which could lead to public health issues and you probably are aware the fact that we do publish this on our website just to give you an indication as to where the applicants where the manufacturers are coming from these figures they go back to 2012 they’re still basically valid India has is slightly ahead of China at a moment there’s 222 sites China’s are 211 and then there’s a repetition between European manufacturers essentially so these manufacturers they’ve taken a voluntary decision to apply for a certificate of suitability it’s the applicants choice to do so and you can see that there’s a lot of manufacturers in the world who’ve made this decision so we’ve we’ve received over five and a half thousand applications so far and there’s over 3600 valid certificates at the present moment and these these figures obviously did they change we get new applications we issue new certificates old certificates they can die because manufacturers stopped manufacturing and then of course there’s the situation we’re following inspection we’ve had to suspend certificates and I think personally is sort of testing me to the fact that certification is a voluntary procedure but in the last 20 years we’ve got to a state where there’s over a thousand manufacturers who have decided to request our services thank you