Dr. Iris Zieler: Hello. Good morning, everybody. And welcome to our presentation this morning. And I hope you enjoy the views and the breakfast, of course.
And what we'd like to do this morning, my colleague Chris and myself, is just to give you a brief overview on some of the hot topics as to high potent manufacturing.
It's not going to be a long presentation, but because of the time obviously, but we just want to touch on some things. And then you're very welcome to ask all kind of questions afterwards. And we can discuss in detail.
So, what we'd like to do is just give you a brief overview on what kind of market in the pharmaceutical area are we talking about and what are really the prob--or the challenges we are facing.
And you see here lack of harmonization. That's really one of the big challenges we are facing.
Briefly touch about manufacturing, so the regulatory facilities, SHE aspects, and then just a few slides as kind of an outlook on what does that mean for development and bringing quality by design and containment together really.
And then I'd hand over to my colleague Chris, who is going to talk about the outsourcing perspective and what Corden can do, what capabilities we have in that aspect.
So, what kind of market are we talking? And there's quite a few reports. And they are not all consistent in, like, the exact figures. But, basically, the trend is that almost a quarter of all new NCEs in R&D are going to be highly potent compounds now.
And especially if we talk about oncology, it's more than 50 percent or close to 60 percent of the compounds being highly potent.
Transferring that into dollars, that is a number of 2.4 billion in 2011. But, it's increasing steadily. And the perspective is it's going to be more than 5 billion by 2018, increasing further to more than 7 billion by 2022, so really a growing market.
And also, for the contract manufacturing market, the revenues--and that's all high potents, not just the oncology drug substances--was about 3.25 billion in 2011. And also, here, the perspective is going to grow.
So, a growing market, good. Growing income, revenues, great. But, what are we talking about? What--why is it that we have this increased demand of highly potents?
And there's basically two driving factors from the therapeutic area, which is more highly potent compounds administered at low doses in order to treat diseases more efficiently or new diseases.
And then there's the oncology, which we already mentioned. And the difference really is, in the oncology, we're not talking about low doses. Then these compounds are actually administered in rather high doses.
And they have, on top of being highly potent, of course, these other activities, like being cancerogenic themselves, mutagenic, cytotoxics, and so on.
And then on the other side, there's the increasing awareness in all of us in the public that a long-time exposure to these compounds to healthy people to the environment, of course, is really dangerous.
And also, an increasing public awareness of these risks we are facing, and so, every country now has to have increased regulatory and safety health environment aspects to be handling these compounds.
And there are the barriers here. Basically, as I already mentioned, it's the lack of harmonization. It's different for--and especially if we talk about GMP, the regulatory aspects, we have so many different nationalities, and there's no real harmonization. And I talk a little bit on that further on. And the same is true for the safety aspects.
And then, of course, there is the barrier of the highly specialized facilities, the technical expertise you need to work with these compounds, the systems you have to have in place for the waste treatment, for the containment, the costs associated with that, the cost to maintaining these systems, highly trained operator systems. And this is all true, not just for commercial production, but also in R&D.
And then in R&D, there is this additional challenge that we don't really know that much about these compounds in the early stages. But, we still have to handle them adequately.
And if we talk about the drug compounds which we consider highly potent, scientifically really, we should think about two categories. And there's the one category of compounds, and it's not associated to, like, classes.
But, it is, as you see here--can't really show here--it's different kind of molecules going through all therapeutic areas. And even cholecalciferol is considered highly potent. But, all of them have a threshold value.
And then there's the other class, where we have highly sensitizing compounds or compounds without a defined threshold value. And these compounds definitely need to be treated differently, whether if they have a threshold value or not.
And in this compound class, we have of course the well-known beta-lactams, certain cytotoxics, especially if we talk about alkylating substance, or with living organisms.
So, that's the two categories from a scientific point of view. But, if you now look to the regulatory landscape, there's no harmonization. And it's not really so far been addressed in that aspect.
Coming from Europe, of course, from my plant, the European regulation is the most important one. And in Europe, it is covered by the current GMP guidelines, which is chapter three and five, dealing with the high potents and the cytos.
And this is the good thing about these guidelines right now because there's a new draft and which is going to come into active or going to be active by March next year and going to address this for the first time really in detailed way scientifically, whereas the FDA has always used that risk-based approach and--but, of course, only concerning the cross-contamination.
ANVISA does not define--ANVISA is the Brazilian authority. They do not define highly potent at all but have a clear saying in certain classes, and that's hormones, need to be separated without any further discussion really or rationale behind it.
And then Japan, rest of the world is still different stories.
So, in Europe, so far, the Chapter 5.18 was defining--this is now difficult really--the certain hormone cytotoxic and other highly active materials. And here, we have kind of this vague definition again that, in order to prevent cross-contamination, they have to be either produced in segregated areas, or they can be manufactured by campaign, separation in time.
So, but, now, how--what I'm going to do? It's not a clear guidance. And this is really what's now going to change with that new draft, the guidance here, where there's a clear definition based on toxicological evaluation.
So, it's signs based, risk-based approach coming back. And based on this quality risk-management system, you come out with a clear threshold value. And if you can meet that, you don't need dedicated facilities, while you still have to have dedicated facilities in the cases where you cannot adequately control by operational or technical measures or where the scientific data do not support a threshold value.
And that's, again, the beta-lactams, of course, or where the threshold value is so low that you don't really have--you're below the level of detection. And that's the scientific rationale for it.
So, there's a couple of definitions going along with this guidance you have to know when working with it. And they're sometimes a bit confusing.
It's the so-called permitted daily exposure, which represents a substance-specific dose where there is, even for long-time lifetime exposure no risk associated with it. And that is based on the NOEL, where this is a toxicological value, where there's no critical effect observed in the animal species. And you always take the lowest one. And that's where the PDE is based on.
Not to be mistaken with the threshold of toxicological concern for genotoxic compounds because this is still a different story because, there, you don't really have a threshold, again. And then these values have to be much lower.
And just for the completeness, there's, of course, other abbreviations, definitions used by different organization. And the acceptable daily exposure is basically the same as the PDE, but it's coming from the ISPE. So, it's a different wording.
Well, this is the GMP. But, now, we're talking about the safety also. And again, here, we have classification system, terminology. And the most common terms are really the OEL, which is the exposure limit for the occupational exposure and then the occupational exposure band.
Basically, the difference is, if we talk about a specific value, which is micrograms per cubic meter, exposure over, like, a week, eight hours a lifetime, whereas the band is pulling them together and say, like, okay, they're not the same, but within this band, the same technical precautions are adequate to control it.
But, unfortunately, again, we have different systems. And there is the most well known, of course, with the Safebridge system categorization.
But, for example, in Germany, and that's the lower part, there's--from the occupational health system, there's a different classification. And it's not matching. It's not so far apart, but still, it's not matching.
And then some companies, like the big corporates, they have their own system.
We all use the categories 3, 4, 3b, but it's different OEL values behind. So, we have to be careful if we talk about OEB4. Is it the same OEL value we're talking about?
So, stepping onto the next topic, we had covered the GMP, the safety, how to do or to actually maintain or achieve all of that during the manufacturing.
And there, we have to have methodologies and processes in place to ensure the cleaning validation or verification, the OEL monitoring, and of course, the environment safety and waste management. And our facilities have to be designed in that aspect.
And again, I would propose, and I really like that slide, which I borrowed from a colleague, who gave their presentation last year in a workshop, to do that risk-based approach.
We have to consider what are we talking about. And the risk increases when we go from short exposure to long, from small quantities to high, from mild potency to high.
And here, we have the drug in its dosage form. If it's a coated tablet or a liquid, the risk is obviously much lower than if it's a powder.
And the same risk increase is true to our facilities. If we contain it, the risk is rather low. If it's an open system, of course, the risk increases. And that's what we need to assess in order to see how we're handling and how we're assessing certain compounds.
And then it's, again, a question on how much of this compound is in the actual dosage form or the intermediate in order to assess the risk for this handling step.
And as I already mentioned, the dosage form has a huge impact. So, for highly potents, you don't really want to have a uncoated tablet or a capsule that can break and, via the spillage and during the handling, really exposes a risk to the environment for safety and also cross-contamination.
And the same thing you have to do again when you think about packaging. If we talk about a film-coated tablet, for the packaging, there's no big risk left, also taking, of course, the other aspects into consideration.
If we talk about a capsule, you still have to treat it as a high potent.
And I'm not going to go into this in detail because I have another slide just in a minute. But, there is a lot of words and abbreviations used, like HVAC system. We have segregations. We have barrier systems. We have cleaning in place. All of these are aspects you need to consider.
And they're associated, of course, as I just mentioned earlier with costs, building them, maintaining them, operating them, having the systems in place to make sure it's all working properly.
As a conclusion, you could really say, and that's today's state of the art, you want to contain your product, your compound in the system and not just protect the worker.
And in that aspect, we talk about two classes of containment. There is the primary containment, which contains actually the compound in the system in the machine.
And there's a lot of different--there's just a couple of pictures here. There's a lot of technical solutions out there. What you have to be aware is the technical solution has to be adequate for the potency of your compound, of your drug product, for the risk, which is still associated with it and, as you see here also, for the scale.
If we talk about small quantities, we can still handle them in a fume cabinet. If it goes up, we really need to have this restricted access barrier systems to, like, lab scale.
We talk about isolator systems, if we go to pilot scale, or even then already closed systems. But, for commercial, we definitely want to have closed systems.
Whether it's a rigid or flexible containment doesn't matter. And that again, this is depending on the process, on the potency.
What you have to ensure is it's adequate for the risk ranking that you have assigned to it.
And then, only after that is the secondary containment, where we contain it at least in the area in the room in the building and if it's escaping from the primary containment.
But, as I said, this is only the second choice. And depending on how good your primary containment is, the measures you need for the secondary containment, of course, are different.
And in this aspect, secondary containment means that we have the Atric system, which is separated air handling, heating ventilation systems. You have that one-directional flow of air that everything goes in only once. It's not recycled. You filter it, your air that comes out.
You have the pressure systems to have everything locked really into the lowest pressure that--and overpressure on the outer areas.
You need to talk about decontamination. Everything that goes in, if it's workers, if it's product being potentially exposed, needs to be decontaminated. And you have to document that, validate that.
And then you have to collect whatever comes out and treat that properly, whether it's water, whether it's effluents, whether it's heating fluids, whatever.
And I know that's just a quick overview, but I don't want to spend too much time--of your time. I was talking about GMP earlier. Here, we come back to GMP because it doesn't help us to have a PDE value defined. We need to verify we can meet it and we can meet it constantly.
So, that means we have to do proper cleaning validation. And--but, using that PDE value is really something we can now demonstration. We clean down to that value. We document. We routinely meet it. We validate that. And then we can work in shared facilities.
And of course, there's a lot of safety factors I'm not going to discuss here in order to make sure that PDE value is really safe.
If we talk about R&D, cleaning validation is not always possible because, sometimes, we just have it in there once. So, in that aspect, you need to do absolutely 100 percent verification of your cleaning processes.
And then finally, GMP meets SHE again because it's not only surface-borne cross-contamination we have to worry about. It's also airborne cross-contamination. And that's where the safety also comes back in.
And what we do in order to control that is continuous OEL measurements. And if you talk about containment, then your technology really needs to ensure everything is contained. But, never the less, you need to document that, validate it's working. And you have to do that for the different risk categories, compound classes.
And only then can you relieve your workers of the protective equipment. If you have only partial protective containment, then you have to do even a better, a more intense monitoring that nothing is escaping to adjacent areas with people not protected in there.
And what you have to do is really a risk-based--and that depends on the methodology of containment. You have a risk-based plan how you do your OEL monitoring. And that's required not only from a GMP aspect, but also from a safety aspect in most countries now.
So, here, the two really come together, but again, coming from different systems and regulations.
And yeah, I've mentioned that before. Of course, we also have to worry about what comes out, whether it's water, and there we have the aquatic life risk, which by the way is not just available for highly potent ones, but also others, about cleaning effluents, how we treat it, how we dispose of solid waste, how we filter our air.
And all that needs to be an integrated system in place within the company. And we have to document it.
And nowadays, coming all together, I mean, we're all used to GMP audits. But, if we talk about highly potent, we also have to do the same for the safety health environment.
And the big companies are actually doing it. When they come and audit us, it's a GMP audit, and it's an SHE audit.
So, the last few minutes I'm just going to spend on quality by design. And we've all heard that during the conference, again. Now, it's in everybody's world. We talk about quality by design development. But, why is it so important if we talk about QbD when we talk about highly potent compounds?
And I mean, this is a graph I think you all know very well. We have to have a control strategy in place, which is based on a risk assessment and a further scientific understanding. And that needs to be developed in rather than just tested in, in the end, and to ensure continual improvement by that way.
But, if we talk about highly potent, we have to be aware--in a containment, that's what we want. We just said we want to have it at primary contained. But, that means we don't really have access. We don't see what's happening, especially if it's like rigid containment.
We have limited access to sampling points to IPC controls we can do. And this is an important thing not everybody's aware. We have long distances, transfer systems, which impose additional stress on our process. It's a risk factor. And we need to control that.
And if something goes wrong, we can't really interact because, otherwise, we have a real safety problem. So, that should be more than enough reason to say where these are processes, we really have to have that further understanding.
We know what our critical process parameters are, what impact our material attributes have. And we use modern PAT tools to monitor and verify continuously that we are meeting that with in-line real-time data.
We have loop controlled adjustments with feedback loops from these PAT measurements. And it's all part of a QbD-based control strategy.
So, pulling that together, it really means you have to have a QbD-driven development first to have a robust manufacturing process with signed spaced limits for your process parameters, your critical ones, and to ensure that way a reproducible meeting of your quality attributes.
And you have to continuously verify that, monitor it during the process real time because that allows you then to have a reliable quality outcome, increased throughput, high planning precision, low waste and inventory costs, and really the safety aspect as well because, then, you don't have the risk of interface with the operator.
And this is really the last two slides I have. This is just part of a case study, just to give you a flavor of how to assess that.
We are not talking about quality by design in PAT, you have to measure everything. But, again, it's a risk-based approach.
And if we talk about containment, and this is a risk-based approach for immediate-release tablet manufacturing. And there's two processes you could consider, the high shear wet granulation, and the other one is a direct compression.
So, you go through and you consider really what is the risk of the individual process steps as to, do I need continuous PAT monitoring, even in commercial after having done a quality by design-based development, or can I say I have enough data, I don't need to do PAT?
And of course, green means in that aspect not necessary, yellow to be discussed depending on the drug product, and red you definitely should do that with a PAT monitoring.
And then that's what you design your plant, your process flow for, to have PAT installed in these critical process steps or the dispensing of the excipients. You need to make sure it's the same--the right grade with the right particle size of the excipient you want to use.
Same true for the API. So, you have to have PAT monitoring during the dispensing.
Then this is here the granulation, which was a wet granulation where we said for this product it's not a risk. So, there's no PAT control here.
The drying is critical because the endpoint residual moisture is critical. And there needs to be a feedback loop that the process stops when the correct residual moisture content is achieved.
Then the transfer with the dry sieving, again, uncritical. But, here, the blending process, of course, blending is always a critical process step. And you need to have an endpoint control whether your blend is homogeneous.
And then finally, the compression where you want to have a really real-time control on, are you meeting the API content, the assay in the--the content uniformity in your tablet, the dissolution properties? And that can also be done by PAT.
So, in that aspect, the whole plant can be designed for a process in a specific product and with enabling in a PAT technology, or you don't need it for another product. But, you have to do that risk-based approach.
And that's just summing it up. And I'd like to hand over to Chris, my colleague, for what are you doing if you want to outsource that process?
Mr. Christian Ahlmark: Welcome, everybody. We'll just wrap this up. A little bit regarding the outsourcing aspect of this work and who are the companies that are involved in high potent API manufacturing and drug product manufacturing.
Of course, there's pharma companies, but a majority of the stakeholders out there are the CMOs.
And why is that? Well, you know, some of the strategy for outsourcing with pharma is that, you know, there's limited in-house capability. There's, you know, the expense involved with new facilities. There may be lack of expertise within the pharma company. It's not their core expertise.
And then all the requirements that Iris mentioned as far as the increased environmental health and safety and GMP requirements that's involved.
With selecting CMOs besides the typical vetting process that you have with a CMO, you know, you're looking at their capability and capacity.
But, in this instance, you're also looking at, you know, what kind of controls does the company have in place? What kind of cleaning procedures do they have? You know, what kind of systems, SOPs, and also risk assessment tools?
And what's their history? What's their history of inspections and maybe even history with other companies and other colleagues?
So, a little bit more involved when you are outsourcing because, if you're a pharma company, you're taking on that risk, whether it's internal or if you externalize it.
A little bit about Corden, to say least, we have a very large stake in this market. We have nine facilities across the globe. And 30 percent, three of them are in the high potent area and cytotoxic area.
So, our facilities, you know, cover oncology, cytotoxics, high potent API, as well as high potent manufacturing for a finished dosage product. And I'll explain a little bit about the specifics of those.
So, those three plants that Corden has, one here in the U.S., is the Colorado facility in Boulder, where we do high potent APIs focused on synthetic peptides, high potent APIs, as I mentioned, cytotoxic, noncytotoxic API.
And this is, you know, small scale, gram-scale quantity on up to metric tons, the material.
That's an ex-Roche facility. And it's a very impressive state-of-the-art plant.
Latina, Italy, covers our cytotoxic OEB4 and 5 levels, some of the levels that Iris mentioned. And we cover sterile and oral dosage forms at that facility. It's an ex-Bristol-Myers site in Latina.
And then the Plankstadt site in Germany covers high potent APIs, cytotoxics, and on final dosage forms and the solid dosage form area. And I'll explain a little bit more about those sites.
At Corden in Boulder, Colorado, as I mentioned, it's API, various technologies, a lot of experience, 30 years of experience at that site with isolator technology. We can get down to under one nanogram per cubic meter OEL levels and also under 10 nanograms per cubic meter.
We have separate development laboratories there and provide small-scale, pilot-scale synthesis on up to commercial-scale synthesis at that facility and then filtration, whether it's high-pressure or low-pressure chromatography and ultrafiltration and diafiltration.
And then some of the engineerings involved--engineering controls in place, whether it's drum container systems, powder transfer systems, glove box, flexible intermediate bulk containers, and local exhaust ventilation.
And then in Latina, as I mentioned, that site covers the sterile dosage forms as well as solid. And we do capsules, tablets there. And then in the sterile area, we provide ampules and vials and also liquid and lyophilized capability at that site.
And additionally, we've done a lot of investment in the past. And then recently, we added new lyophilization capabilities. And over the next year or so, we're going to be adding more sterile lines at that site, both aseptic and terminally sterilized.
And at the Plankstadt facility that Iris works in providing solid dosage form capability, small batch sizes on up to 200 kg batches, and we have a QbD approach. And we handle that even from R&D projects on through to the commercial and tech transfers.
We have two different R&D labs handling from 100-gram quantities on up to 5 kgs and a second lab up to 20 kgs and various capability handling early Phase I through Phase III, submission, and then commercial manufacturing at that site.
And then the packaging, your typical blisters and bottles for solid oral, and they're all approved by all the regulatory authorities, EMA, FDA, ANVISA, and Japanese authorities.
So, really wrapping, as I mentioned, Corden has a large stake in this market, both from an API perspective and also a finished dosage form perspective.
We've invested a lot of money and specialized technologies and have over 40 years' experience in that industry in Europe and also in the U.S. All the sites have been audited by the authorities.
And we're trying to provide an end-to-end solution to take, you know, customers from their early API through the development and eventual commercial manufacture of the material.
So, with that, like to thank you for joining us today, taking time out of your busy schedule, and hope it was informative, and we'll have some questions at the end.
Thank you.