Unlock the Digital Signature Legitimateness for Pharmaceutical in European Union

How to eSign a document: digital signature legitimateness for Pharmaceutical in European Union

welcome to this chapter on good manufacturing practice EU and USA GMP in this chapter we'll explain how GMP is structured and how it works in both the European Union EU and the United States of America USA in particular we'll focus on how both consider the concept of quality and quality management in chapters 2 to 4 we have looked at the evolution of both contemporary quality and quality management system thinking so far we have talked about quality in general terms and looked at how leading industries and experts view quality ie experts from outside of our industry now we should take our own industry forward and we'll begin this by exploring good manufacturing practice the very essence and cornerstone of quality thinking in the pharmaceutical industry and see what it says about quality and quality management systems just before we do this we should examine how GMP works firstly in the European Union EU and then the United States of America USA all countries or sometimes called member states of the European Union must work to the principles of EU GMP EU GMP first came into existence in 1992 when the single market was created within the EU prior to 1992 countries had their own GMP s and were inspected by their own national regulator Authority if you supplied multiple countries across Europe then it was likely that you would inspect be inspected by regulator Authority inspectors from each country to which you sold product with the creation of the single market of 1992 all national GMP s disappeared an EU GMP was born from this point onwards manufacturing sites across the EU would be inspected by their national authority on behalf of all of the EU just before 1992 two new GMP directives were issued from the EU these contain the high-level legal requirements for pharmaceutical manufacturing sites across the EU to work two one was for human medicinal products ninety one three five six IEC and the other was for veterinary pharmaceutical products 91 four one - EE C and the requirements of both were more or less the same but with some subtle differences both of these directives are European law and must be incorporated by member states into their own national laws the human medicine product directive was subsequently updated in 2003 ahead of the introduction of the clinical trials directive this changed the wording of the directive to cope with those subtle differences implicit in the making and packing of clinical trial materials as opposed to conventional medicines the updated directive was 2003 94 EC and this is the current directive that manufacturing sites must work to when making pharmaceutical products in the attachments part of this presentation you will see a PDF copy of both the human and veterinary directives choose the directive that is relevant to your manufacturing site and open it up and/or print it off now note there is no need to fully read these directives we just want to show you how they are structured and roughly what their requirements are as you look at the directive you'll see that it contains a series of articles all of these articles are EU law and must be implemented by pharmaceutical manufacturing sites or manufacturing authorisation holders to be precise the first two articles are administrative article 3 makes it a legal requirement that manufacturing sites are inspected article 4 makes it a legal requirement that manner pattering sites work to GMP an article 5 makes the legal requirement that manufacturing sites make their products as described in their marketing authorization we will now focus on the human directive 2003 94 EC but you should note that the same principles apply to the veterinary directive 91 for 1 to e ec article 6 onwards are the main principles of EU GMP these can now be seen from article 6 to 15 note that article 15 on labeling of investigational medicinal products i mps used in clinical trials is only relevant to human medicines and is not in the corresponding veterinary directive all of the articles in the directive are law and if a manufacturing site is not following any of these requirements then they can be taken to court and prosecuted an example of one of the articles article 6 on the quality assurance system is shown this is very relevant to this course it states that the manufacturer shall establish and implement an effective pharmaceutical quality assurance system involving the active participation of the management and personnel of the different departments this is the very first key principle of GMP you must have an effective QA system that actively involves everyone one of the problems of the articles of the GMP directive is they lack any real detail about how to achieve the requirements of each one in order to assist us the EU has produced a guide to GMP that sits next to the GMP directive there are nine chapters in the EU guy to GMP and you can see how each chapter corresponds to an article of the GMP directive this the case for all of the articles except article 15 as this Court is being written 2013 the titles and contents of a couple of the chapters chapters one and seven have been updated to give greater scope to the areas that they cover for completeness the full list of chapters by their new names as of January 2013 can be seen on the right hand side the repercussions of this update will be examined in unit 2 it is a legal requirement that manufacturing sites comply with all of the articles from the GMP directive it is also a legal requirement that they were to GMP GMP directive article 4 but the guy to GMP is as it says guidance where there is guidance then there is scope for flexibility something that we'll come back to shortly the nine chapters of EU GMP are rarely updated however unusually a number have just been it reviewed or a due to be updated in 2030 in 2014 sitting behind the nine chapters of GMP are a series of annexes these provide additional GMP guidance for certain situations and are used when they are relevant as with the nine chapters of GMP these are guidance documents - they can be seen it is the annexes which are updated or added too frequently with the nine chapters rarely updated - strange anomalies occur within the annexes firstly there is no annex 18 this was originally entitled GMP for active pharmaceutical ingredients or API GMP and was a separate GMP guide for the manufacture of the active chemical in a medicine the was later moved at it did not apply directly to conventional GNP for finished product manufacture API GNP was therefore moved to a newly created part 2 of GMP with conventional GNP the nine chapters that we have been discussing forming part 1 ii anomaly concerns what was going to be annex 20 and 21 in some EU countries such as Germany for example they have chosen to go further than expected by the EU and have made all of the chapters and annexes a legal requirement this is not the case in all Member States such as the UK where the chapters and annexes are guidance it was not possible to make the contents of what was going to be annexed when T and 21 into law and a search these will no longer be annexes they have been moved instead to a newly created part 3 of GNP in 2012 so in summary EU GNP now consists of the following part 1 the 9 chapters of GMP part 2 GMP for active pharmaceutical ingredients and then there are all of the annexes which are applicable to both parts 1 and part 2 of GMP finally there is part 3 which includes a number of GMP related documents such as quality risk management pharmaceutical quality systems and guidance on site master files plus a few other documents all of these documents can be obtained for free from the European Commission's you'd relax website google you jel X volume 4 or go to the website link in your notes now if you understand this then you're doing very well by the way in the UK the regulator of for the medicines and Healthcare Products regulatory agency or MHRA publish a book about every five years with relevant GMP related rules and guidance commonly referred to as the orange guide it contains all of the EU GMP chapters and annexes that a week that we have been discussing it also includes good distribution practice GDP and a range of other related EU and UK rules and guidance for pharmaceutical manufacturers and distributors so in a nutshell we have seen how a EU GMP is structured and how it works at this point it is worth reiterating an important point and one often missed by organizations and regulatory inspectors alike it concerns the fad that the chapters of EU GMP are guidelines and where there are guidelines then there should be flexibility this is supported by the final paragraph in the introductory chapter 2 EU GMP where it states the following it is recognized that there are acceptable methods other than those described in the guide which are capable of achieving the principles of Quality Assurance the guide is not intended to place any restraints on the development of any new concepts or technologies which have been validated and which provide a level of quality assurance at least equivalent to those set out in this guide in other words there are alternative ways of achieving the same result and you are allowed to do things differently to a way prescribed in the guide as long as it is at least equivalent and validated an example of this is having electronic batch records rather than paper-based records in the United States each government department has its Code of Federal Regulations or CFR the Food and Drug Department has volume 21 with other volumes belonging to different departments such as transport education and so on within volume 21 are parts 210 and 211 and these contain us a GMP part 210 is more of a preamble and the actual requirements of us a GMP are found in part 2 11 the content of 21 CFR 211 is shown it is not wholly dissimilar to the contents of EU GMP the full name of USA GMP is 21 CFR part 2 11 current GMP for Finnish pharmaceuticals 1976 and is the legal requirement for medicinal or drug manufacturers in the United States note that there is no chapter within us a GMP on quality management it was issued in the 1970s when we were in the quality control era and in fact there is no mention of quality management or Quality Assurance in 21 CFR 211 whereas EU GMP updates have largely been achieved through the addition and update of the EU GMP annexes us a GMP updates are achieved through a variety of mechanisms these include the following the Federal Register is a daily publication of updates to US laws if there is an update to any part of any of the CFR's then this is published in the Federal Register along with background information as to the reason for the update this update is then formally incorporated into the CFR at the next full republication on the first working day of April every year updating elements of GMP via the Federal Register thus allows parts of 21 CFR to Navan Tuvia to be updated rather than the whole document in one go there have been a number but not a great deal of amendments to 21 CFR 211 since 1978 via this route so you need to always refer to the latest version of the CFR to be up-to-date FDA guidance documents these are the nearest equivalent of EU G MPs annexes and give the FD a is opinion on best practice on a certain subject such as dealing with sterile drug products produced by aseptic processing general principles of process validation and quality systems approach to pharmaceutical GMP regulations these documents are not a legal requirement but do give the FDA's opinion on the subject in effect they do become part of the pile of GMP as it would be a brave pharmaceutical manufacturing site who chooses to ignore what the FDA view as best practice further update mechanisms include the use of FDA inspection guides these provide guidance to FDA inspectors on how to inspect parts of a GMP facility with guidance documents for example on high purity water systems pharmaceutical quality control laboratories and sterile drugs substance manufacture while it's no longer published and not a legal requirement these guides while stated do contain some general principles of best practice inspection findings and warning letters findings at inspections that are not dealt with to the satisfaction of the FDA eventually come into the public domain via the issue of warning letters this occurs when a site is not deemed to be taking suitable actions to deal with inspection findings pharmaceutical manufacturing sites that supply the USA usually employ someone to keep track on what is being observed by inspectors so that their own do not encounter similar findings as you will have worked out by now u.s. AG MP expectations are not as easy to find and are certainly not published in a single book as in as in the case of the EU so in summary we have discovered how both EU and USA GMP are structured and updated while it's different it is worth remembering that the aim of both GM peas is the same to protect the patient we have seen how the issue of updates are tackled in EU GNP this is mainly via the annexes especially important to us during this quality management system course will be the actual contents of GMP part 3 guidelines on quality risk management and quality management respectively in USA GMP we see a more disparate approach and a multitude of documents again important to us and this course will be one of the GMP guidance documents concerned with quality systems both of these update documents will be examined in more detail during unit 2 as we think about the design of a pharmaceutical quality management system for further information on both aspects of EU GMP and USA GMP follow the links given in the chapter and visit the respective you'd relax and FDA's websites this concludes this chapter we're have introduced the structure and legal status of GMP in the next chapter we will look at what GMP actually states with regard to quality management systems