[Music] welcome everybody joining me in our webinar about the basic principles of GMP M first of all to just give you the big picture this webinars planned as really a basic introduction in the main parts of existing GMP guidelines we want to first of all just to give you a basic understanding what does the affirmation mean and then I'm going to give you a short overview about where does it all come from then there will be a part about I'm gonna just give you just the brief picture about the different guidelines in different countries and where GMP is there will be a really brief and short overview about the most important parts at least in our view of the existing guidelines they'll focus on the FDM fdac GMP guidelines and european oil our legs GMP guidelines and finally I will give you just a brief outlook on what we are planning in our next webinar in this series which will focus then on a T and P which stands for advanced therapies medicinal products and as mattina already mentioned before at the end there will be the opportunity for a quick and short question and answer session so let's move on we got a quite packed agenda what does GMP stand for well this is really easy of course it's the good manufacturing practice and if you look at the GMP guidelines especially in the United States you will find the application cGMP which stands for current good manufacturing practices but these abbreviations basically mean more or less the same where does that come from it doesn't came out of nothing and of course there there is a history of GMP and thus history starts as I will tell you pretty shortly in in the early 20th century and what we are seeing in regards of this history is a classic example of a reactive government so there have been adverse events they have been catastrophic events and this led to the implementation of certain guidelines and this is what I'm going to show you right now I'd like to start with these two pictures on the left hand side this is the title of the back then Colliers magazine which was a so-called muck raking magazine today we would call this investigative journalism and they in 1906 had this picture on the title and there was an article series which featured the great American fraud as they called it payton mega medicine patent magazine basically was just quackery and one of these patent medicines was back then some elixir or a liquid which was called his own and which was marketed as antibiotic but which contained since there was basically no regulation at all 98% water and a little bit so frog or sulfurous acid and on the right hand side there's the box of radio dying pills which were marketed as containing the strength of iron and the energy of radium which is of course atomic energy so radioactive radiation which is pretty harmful as you all know but on the package it says carry this and I'm going to show you in a second carry this package with you always this was simply not regulated and and as you might all know this led to two injuries and maybe even deadly radiation events so obviously was the need for further guidelines and for law for laws which govern not only medicines or drugs but also food in 1906 Upton Sinclair published a novel which was called the jungle which basically and mainly covered the work in in slaughterhouses in the Chicago area and this led to a public apprising due to the conditions which their meat was produced and this Public Act rising then helped in 1906 once again to install the Pure Food and Drug Act which was nothing else than just a labeling act this act meditated the the manufacturer of drugs and food to correctly label this act but it only not only had a part upon labeling it was also and is also considered as the birth of which is now more or less the modern FDA then nevertheless there were several flaws because Beauty claims were not limited and it did not require pre market inspections or Hoover but with this act the it was basically leading the creation of the fewer Food and Drug Administration FDA it was initially the Bureau of chemistry which regulated the food and safety but in 1927 and this was in the aftermath of the Food and Drug Act the bureau was reorganized into the Food Drug and insecticide administration in the Bureau of chemistry and soils and finally in 1930 the FDI area the Food Drug and insecticide administration was renamed FDA but still there was no GMP and it took another few catastrophes until the the now modern or GMP canals were installed one of them was the Xillia sulfonamide M incident a company marketed this alexia sulfonamide as an antibiotic but unfortunately they used each diethylene glycol which assume which is poisonous to humans and other mammals as solvent for the self an amide to make this Alexia more tasteful and they added a raspberry flavoring but still since the ethylene glycol was used as a solvent this led to the poisoning of roughly 100 people and the death of 100 people in the United States and in the aftermath the Federal Food Drug and Cosmetic Act passed which is now still the the base of the existing drug regulation in the United States there has been a funny enough if you want to put it like this there has been a trial in court because the company messenger pharmaceutical company violated the law but the violation of the law was not to kill 100 people but to market this so-called alexia as an Alexia since it contained no alcohol and back then if you want to sell an Alexia it has to contain alcohol so they were not sued for killing on more than 100 people but for for false marketing of this so-called Alexia anyway no real GMP guidelines which brings us to the next value and this is phenobarbital phenobarbital is used to treat and still used to treat and developing countries epileptic seizures travel and sleeping anxiety and so on and so forth but it has side effects for instance sedation and hypnosis and if you overdose it it leads to the depression of body systems and finally to pulmonary edema and death where did this happen in another short sulfa drug sulfathiazole which was once again used as an antimicrobial substance but in 1941 the cypher high ozone disaster led to the death of over 300 people because the manufacturer Winthrop's company didn't follow good manufacturing practices the Safa fire drug was contaminated with this phenobarbital because they did not clean up there or that they did not follow the manufacturing standards so the the people which took the cypher files all were poisoned with with the contamination of full phenobarbital and this finally prompted the FDA to require detailed controls in the production and not only at Winthrop's company but of course also throughout the industry and this was the approach which became finally but not yet not in 1941 the basis for production control standards for all pharmaceuticals but as I have mentioned the this was made them hailed as the birth of the GM piece but still there won't be a regulation issues for the next 23 years and it took another disaster and this time this drug to finally install GMP guidelines what this this is thalidomide or Toledo meat which is known in Europe as contact gun and you all know the content on disaster which led to birth defects of several hundred of children in the 60s in Europe but in 1956 Richardson marrow in the United States applied to sell this phalidomide contagion as Givaudan which was the name in the end which should have been the name in the United States but back then Frances Kelsey which was a new FDA inspector rejected this education and this was quite against some some yeah quite against the the part with the pushing of the pharmaceutical company which were of course wanted the drug to be approved Frances Kelsey had a background and fetal safety since she worked with malaria drugs in the 1940s and she rejected it since there was no safety data on the mechanisms of action as required in the act of nineteen interfere and despite political pressure and six three applications Kelsey refused to approve the drug and as we know right now this was of course a life-saving let's put it like this for many American children your u.s. American Sharon and in the aftermath in the of the tragedy in Europe the so called calf however Harris amendment was finally installed as an amendment to the Food Drug and Cosmetic Act and this amendment required that the manufacturers prove the efficacy of the drugs before they they go to the market and they they report serious side effects it required for the first time that clinical trials as to show the efficacy of the drug and these clinical trials have to be adequate and well controlled and something which is important nowadays more and more the study subjects would be required to give their informed consent then it gave the FDA 180 days to approve new drugs and it required the approval book for the new drugs could be marketed in the United States another point of this amendment was that the FDA should re-evaluate the efficacy of drugs which have already been approved between 1938 and 1962 the FDA was then in charge for the control of the advertising of prescription drugs and it also controlled the marketing of generic drugs to keep them from being sold as expensive medications under new trade names and last but not least it allowed the FDA to set good manufacturing practices for industry and mandated regular inspections of production facilities so then there was GMP and it was not only in the United States around this time in the late 60s where these regulations were issued but worldwide for instance in 1963 there was a resolution by the World Health Assembly on drug safety and monitoring which reaffirmed the need for early early actions in regard to adverse drug reactions 1965 the European issued the council directive 6565 eec which laid the base for the European GMP regulations there was another law and an act of Parliament in the United State Kingdom Surrey in 1968 so in the late 60s in the early seventies we saw a plethora of regulations and regards of frack manufacturing practices and it's not only one there is not only whu-oh that's not on the European Union that is also for instance the ICF international committee on harmonization switch gather q7 there are GM piece formulated by the Australian Department of Health Health Canada has issued guidelines but it's not only the Western world also in Japan there are GMP guidelines and we do see more and more other countries issuing guidelines how to manufacture drugs and good manufacturing practices so now we have the guidelines but what's in there I will come back actually it's it's everything and this I will show you later what I'm going to show you right now is at least brief overview of a few of the the basic and main parts at least to our understanding of these guidelines and and what's in there this could be only once again said a brief and basic overview since going deeper into it would just be way beyond the scope of this webinar guidelines these guidelines govern the existence of training department and the buildings and facilities are described in there and how they have to be set up Quality Control departments and laboratories are described and how they this has to mean set up QA departments there has to be regulatory affairs department and not only the production that also the development is regulated under GMP guidelines and if you have the final product its described how you have to package and label it validation it's one of the big points in these guidelines and finally receiving and shipping is also something which is covered by the guideline and what we have done now is that we have concentrated on the two major ones so the FDA C GMP guidelines and the auto LX guidelines which are in place in the European Union and first of all coming back to the personal both guidelines state that the personal has to be trained and experienced it's not only training for whatever their you want the training should also be tailored to the function of the person the training has to be conducted by persons who are qualified so before you can do any training you should of course make sure that the person who's the trainer is able to do this training and finally there has to be an adequate number of qualified person supervising the manufacturing processing packaging of course so if you have these trained people if they have been trained by a bonafide person you have to use these people to manufacture process package and hold the products a building's facilities and equipment basically it comes out it's more or less common sense which is written in there if you think it to the end of course the buildings and facilities should minimize the risk of contamination of the material and products they should be maintained carefully cleaned and disinfected this has to be of course being proven inner in records land and we'll come back to this later right now it's it's more important to look at the complete process of manufacturing so the environment which is provided should ensure quality and a maximum protection against animals and other pests and which is something of quite important and in my opinion it should protect unauthorized personnel from entering the manufacturing studes equipment used in a manufacturing processing packaging or holding shall be of appropriate design adequate size and suitable UK to what what this mean for instance the equipment should have inner surfaces this is something which you will see quite often like these stainless steel tanks for for manufacturing because stainless steel is one of the materials which provides these inert surfaces it shouldn't be maintained carefully cleaned and disinfected on a regular basis and once again if you don't write it down it has never happened and this is something I will come back to this later records should be kept of the maintenance and cleaning and so on and so forth one main part of the manufacturing is the quality control unit both guidelines state that there has to be a quality control department in it is of utmost importance that this department as is independent from the manufacturing this department has to check all the that all relevant factors during the production finds of production conditions in process testing and so on and so forth are in compliance with the final specification and last but not least since there is not only good manufacturing practice but also for instance good laboratory practice the Quality Control Department has to follow the SCADA laboratory practice which is mentioned in the FDA cGMP guideline but you will find this references to the quality control unit throughout all the FDA ase GMP guidelines it's a but it's not only mentioned in the FDA a guideline it's also mentioned in there OLX guideline and small s the same as you see here but what's especially mentioned in the European guideline is that the department should have access to all relevant documents concerning manufacturing sampling testing results and so on and so forth and that there should be a long term stability study of the finished product which should be tested in regular on a regular basis by the quality control department and as I have said before if you don't write it down it has never been done records and reports really important you can have the best process ever if you do not write it down it will not be accepted so there has to be an equipment and cleaning look this is once again the FDA SC GMP guideline the components drug product containers closure enablings should be recorded there have to be master production and control occurs in place but not only there to be master records but also each batch has to be the the production of each batch has to be recorded and controlled then there should be a production record revenue and this has to be done by of course the the control laboratories which should definitely record their their efforts and finally distribution records have to be filled in this is also covered in the European guideline but the reopening guideline has kind of other other wordings for it but there has to be site master file which is the document that describes the GMP related activities of the manufacturer but besides this site master fights they have to be recorded specifications manufacturing formulae or processes packaging and so on and so forth this is an abbreviation you will see quite often sops stands for standard order procedures these have to be written down and followed of course and protocol and the European guide and also specifies the record types which have to be done records which provide evidence of various actions taken to demonstrate compliance with instructions certificate of analyzers and this is something important provide which who provide a summary of testing results on samples of products or materials together with the evaluation for compliance to stated specifications and there are reports which should be done that documented the particular exercises projects or investigations together with these results conclusions and recommendations so if it's not very down it has never haven't something which is a little bit special for the FDA cgmp guidelines is a large part on packaging and labeling control there it is stated that material examinations and users criteria have to be evaluated the handling of labeling and packaging material should be documented the material has to be tested and the storage of the material has to be also controlled there are strict guidelines about the issuing of labor and there should be strict control over the exercise of label issuing for the in for use in drug product labeling operations there shall be procedures in place to ensure that correct labels are used and mix-ups are prevented and that they have to be lot numbers issued to have the possibility to trace the history of each and every lot and since there has been another incident in in the United States and 1902 which others are the the so called Chicago tylenol murders where people have died due to poisoned tylenol pills which have been poisoned after they have been manufactured by by the company and these tylenol burners are still not solved in the United States there are regulations for tamper-evident packaging for over-the-counter drugs the drug product inspections has to be done for the packaged and labeled products shelby expand xm9 during finishing operations to provide assurance that containers and packages in the lord have the correct label and there has to be an expiration date on the package to assure that drug products meet the applicable standards of identity strength quality and purity at the time of use another part which is qualification and validation is one of the main focuses in in both the guidelines and volleyer validation is of course one main part of all these GMP stuff if you put it like this and basically qualification and validation activities should be planned this planning should in the end lead to a so called validation master plan and this validation master plan should consider the whole lifecycle of the equipment but not only the equipment also of the whole production process upon this recodification of the production equipment and also the should be done in regular manner and one of the main stairs steps is process validation maybe you have heard of the three production runs which should be done as validation runs before the production process is finally accepted as being GMP this is how it was before but right now with the merging of several and new drugs for instance as mentioned at the beginning this ATM piece advanced therapy medicinal products or human cell and gene based therapies the regulatory authorities come to came to the conclusion that sometimes it's not easy to do this three validation runs but right now the the focus is a little bit changing also to the ability to do in process validation if in in regards of a risk case a risk based approach sorry the manufacturer of the drug has come to the conclusion that it's easier and what leads to and also high quality product if they do in process validation but the test methods have to be validated there has to be thinning validation and finally a change control system should be in place to show that changes to the already validated process do not have an impact on the quality of the existing products and existing process of course but what else is regulated in the GMP guidelines as I mentioned before more or less everything this is the tail of contents of the European guidelines which I have copied just from the internet and to show you that it's really more less everything I have highlighted a few of the contents for instance there are guidelines for the basic requirements for active substances which I use the starting materials in your process but not only this there are guidelines on a manufacturing of liquids creams and ointments and we are still moving on there are also guidelines on setting health based exposure limits for use in risk identification in the manufacture of different medicines products and share facilities and last but not least since I have picked only a few examples there are also guidelines for the manufacture of veterinary medicine products other than immunological veterinary medicine our products and as you might of course right now be able to consider for yourself if they are guidelines for the manufacturing of other than immune on and shiki killed veterinary products you will most likely find also guidelines on a manufacturing of you know logical veterinary medicine of products so once again it's smaller less all in there as mentioned at the beginning of this webinar we are doing a verbenas series and the next part of this webinar series will cover the so called a TMP advanced therapies medicine or products or human cell and gene paste therapy medicine your products which are at least not as tightly regulated as classical drugs for instance aspirin at the moment but there are right now efforts being done to since at the moment there are no dedicated regulations for the GMP compliant manner of these 80 MPs there are at the moment efforts being done to regulate these products according to their through the new needs which are emerged in the manufacturing of these products I have just copied some of the the existing FDA guidance says for industries for instance there is a draft guidance for industry for to show you that it's not completely covered there's a dark draft guidance for industry on the deviation reporting for human cells tissues and cellular and tissue based based products regulated solely under 361 of the Public Health Service Act and 21 CFR part 12 71 once again draft guidance there is another draft guidance for the recommen recommendations of microbial vectors used for gene therapy there is a draft guidance for industry and FDA staff on the meaningful manipulation of human cells tissues and cellular and tissue based products I can go on with this father for instance there's a draft guidance for industry on sa development for mean immunogenicity testing of therapeutic proteins but still nothing really more or less finalized and nothing which covers the complete process and since this has come to the attention of the regulatory authorities not only recently but 2007 where the European Union released the EC guide guideline on advanced therapy medicinal products there's also in this guideline the article 5 on Good Manufacturing Practice practice sorry which stated back then that and now I'm citing the Commission shell after consulting the agency draw up guidelines in line with the principles of Good Manufacturing Practice and specific to advanced therapy medicine abroad so it was only it was already seen back then that there should be guidelines in place which are not yet in place in order to cover this lack of regulation and the European Union started a consultancy process and right now there are some consultation document in place for the good manufacturing practice of advanced therapy many similar products this is the case in the European Union at the moment as I said there are many many guidelines and draft guidelines which cover parts of the process in the United States and this is which we are going to cover in our next webinar and since we have seen this and something which maybe all of us has already have already learned is that translation translational research may start already with the most basic research and experiment you are doing in your labs and maybe you're doing experiments which you have never been imagined to become relevant for the clinics but at least if you are planning to use your research on the way into the clinics plan ahead and find a partner who can support you through all the way from basic research to the p4a through the preclinical phase until your groundbreaking maybe groundbreaking discovery becomes the day-to-day application and connect in life and with this I would like to finish and I'm happy to take your questions [Music]