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1、The CTDMO:A New Paradigm In The Cell And Gene Therapy SpaceIN ASSOCIATION WITHPOWERED BY SCRIP2/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)Service providers to the global pharma-ceutical and biotech industries have become a proverbial alphabet soup in the last decade.Origi
2、nally there were con-tract research organizations(CROs)and contract manufacturing organizations(CMOs).While the distinction between them was sometimes blurred where companies or different parts of larger ones were active in both spaces,it was generally well understood.Recent years have seen the rapi
3、d rise of the con-tract development and manufacturing organization(CDMO),while a few companies now use the term contract research,development,and manufactur-ing organization(CRDMO).Now,we are seeing the rise of the contract testing,development,and man-ufacturing organization(CTDMO),with particular r
4、eference to the cell and gene therapy(CGT)space.CGTs have shown outstanding promise in recent years.They offer novel therapies with high potential success rates and the COVID-19 pandemic has given a massive boost to their acceptance.There are consequently many sponsors with candidates in the pipelin
5、e.One downside of this is that there is a lack of manufacturing capacity in the industry as a whole.Many sponsors therefore outsource their production processes to CDMOs.Testing is a critical capability in this field,both in terms of timeline and quality.It is also a common bottleneck in the develop
6、ment process.Assay validation,stability testing,and potency assays are the most common but there are others,all of which are complex and can be significant pain points in a part of the market where time is the The CTDMO:A New Paradigm In The Cell And Gene Therapy Space3/March 2023 Citeline UK Ltd 20
7、23(Unauthorized photocopying prohibited.)most important criterion.Here is where CDMOs like WuXi Advanced Therapies that offer integrated testing onsite at their manufacturing facilities come into the picture.What Does Integrated Testing Mean?WuXi Advanced Therapies offers integrated platforms to tra
8、nsform the testing,development,manufacturing,and commercialization of CGTs,as well as many other types of advanced biopharmaceuticals.That said,every CDMO in the pharmaceutical and biotech space carries out testing to some degree.So what does the term integrated testing services actually mean in the
9、 context of pharmaceutical development?“What we mean by that is that were able to do full-lot release testing for the most challenging products on-site and in real time,”says Dr.Michael Stump,Executive Director of Testing Operations at WuXi Advanced Therapies.“We have clients who manufacture both in
10、ternally and externally.For our internal clients,we do everything at a single location.That means we dont have to ship any material for further testing when manufacturing at our site.”This capability,Stump adds,is not unique to WuXi Advanced Therapies,but it is certainly not common either.Particular
11、ly in the CGT space,the need for integrated ser-vices has been widely rec-ognized but service provid-ers have generally focused more on the manufacturing element as they scaled their offerings to address the development boom.“Along the way,I dont think the industry was as cognizant about testing,so
12、the testing piece has lagged a little bit compared to the amount of scaling done on the manufacturing side.”“The element that really makes WuXi Advanced Therapies different,”adds Dr.Heather Malicki,Executive Director of Analytical Development and Testing Technologies,“is that we started in the testi
13、ng business and then built out the manufacturing business,so it was fully integrated from the beginning.What weve done is to really try to localize because of how quickly CGTs have to be released on demand.You really need to have all of the testing located at one site.”As Malicki explains,the compan
14、y has been actively replicating or moving specific laboratory services from other WuXi Advanced Therapies sites across the US into its main Philadelphia site,thus enabling it to carry out all of the testing required for CGT batch release.Again,this kind of one-stop shop is neither new nor unique,but
15、 it is a huge advantage in the CGT space because speed is so much of the essence here.“What we used to have to do in 72 days,we now have to do in 72 hours.Because of that time constraint,shipping to a second site is just not feasible,”says Stump.WuXi Advanced Therapies other unique selling point,acc
16、ording to Malicki,lies in having its subject-matter ex-perts(SMEs)readily available and part of the development and release teams.“We have“Testing is a critical capability in this field,both in terms of timeline and quality.”4/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)SME
17、s that come together in core team meetings for our manufacturing programs all across the different stages of those programs,”she says.“They can work together quickly and develop appro-priate sample plans with the process engineers and pro-cess scientists.So its really a harmonized workflow.”One-Stop
18、 Shops PreferredIn other parts of the pharmaceutical development market,there is still some resistance among purchasers towards using a one-stop shop,generally because they prefer to mitigate risk by using multiple vendors with different levels of capability in different techniques.In CGTs,and indee
19、d on the large molecule side generally,however,clients more often prefer a one-stop shop.There are sound reasons for this.CGT sponsors who have used multiple vendors have sometimes experienced delayed turnaround times,and the challenges of inconsistent testing and/or different project management pro
20、tocols.Above all,because time is so critical in this field,the vast majority of sponsors see the value of a vendor who can provide testing at a single site in terms of streamlining the process.“In CGT,its just easier not to have to ship material around and the quantity of material to be tested is a
21、lot less.Its easier to go to a one-stop shop,”Stump says.“Its also easier for a vendor to stay with one group from a quality perspective.For those who are going to multiple vendors it is more of a risk mitigation when,if its a large company,they want to make sure they use multiple vendors who can su
22、pport them in case they have surge capacity.”“This tendency is largely a result of the specific needs developers of CGTs have when it comes to testing services,”Stump adds.“The thing I am asked most often is How fast a turnaround time can you get it to me in?”.WuXi Advanced Therapies is currently wo
23、rking with nearly 200 clients and this observation holds true across the board for essentially all of them.Timelines are very short in this area.“The next most important concern is the quality of the testing and the product,”Stump continues.“Other important drivers are the vendors capacity and commu
24、nication during that timeline.Cost is a distant fifth.Its usually in that order in the CGT space.Time and quality are the two key driving factors.”Updated CapabilitiesJennifer Cheung,Vice President of Quality Assurance and Regulatory Affairs at WuXi Advanced Therapies,adds that the company offers pl
25、atform assays to its CGT clients,on which they can develop their own particular specifications.“Sometimes when they come to us,they dont know what to include,”she says.“We know different aspects of the technology,from very simple parameters like physical appearance to very“In CGTs,and indeed on the
26、large molecule side generally,however,clients more often prefer a one-stop shop.”5/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)specific ones like potency assays.We have off-the-shelf assays that we can recommend to our clients,which will definitely help them to speed up the
27、ir development as well as getting their GMP batches ready for release and for submission.”There are no significant gaps in WuXi Advanced Therapies CGT testing capabilities that need to be plugged,Malicki says,but the technology continues to evolve rapidly,and the company is continually monitoring an
28、d attending conferences to ensure that it has the latest technology.It is also actively working on the automation of its assays.“We do offer some testing thats automated,but we are continuing to build in that area because we are seeing the efficiencies and the improvements that automation can bring.
29、Are we fully automated yet?Not quite,but its a work in progress and weve definitely seen the benefits of automation,”she says.WuXi Advanced Therapies has recently developed novel customer-specific analytical methods for advanced therapeutics.Much of this,of course,is subject to confidentiality agree
30、ments but techniques used have included flow cytometry and droplet digital PCR.It has also been active in the development of product-specific potency assays,which it has transferred in from clients and performed successfully.“We have platform assays that we have put online to assist our clients who
31、need potency assays,”Malicki says.“We have some general potency assays to get some of our earlier-phase clients started,then we partner with them to ensure that we can then move away from a generic assay to a very specific one,and we work with them to do that.So we do have the experience.”Lot releas
32、e and viral release testing are two other key capabilities.Stump says that the company can offer some of the fastest turnaround times in the industry on these.Running Fast To Keep UpRegulation is always a major challenge in the pharmaceutical industry,nowhere more so than in relatively new areas whe
33、re the technology is changing rapidly,and the regulatory environment is uncertain because regulation has lagged behind the technology.Small sponsors in particular lack the in-house capability to cope with the burden,particularly when it comes to Chemistry,Manufacturing and Controls(CMC).A recent sur
34、vey by Citeline found that 94%of respond-ents considered regulatory support from a vendor either very important or some-what important to them.1 Increasingly,regulatory sup-port is seen as something that should be offered as standard rather than a val-ue-add.This will continue to be the case even mo
35、re as the technology advances and becomes more complex.CGT is no exception to that rule,but there is a fine line to be negotiated between“WuXi Advanced Therapies has recently developed novel customer-specific analytical methods for advanced therapeutics.”6/March 2023 Citeline UK Ltd 2023(Unauthorize
36、d photocopying prohibited.)what the client is looking for and what the regulators are looking at.“One of our complexities in working with different regulatory agencies is that they like technologies that are tried and true,something that has ten to twenty years of data,”Stump observes.“Yet at the sa
37、me time were in an industry that wants everything to be new as possible.If somebody authors a paper about a new technology,everyone says OK,do you have this yet?Theres always a balance to be drawn between what is tried and true on the one hand and what is up-and-coming on the other.”Specifically in
38、the area of CGTs,because the regulations are still evolving and requirements from different health authorities can be drastically different,clients have sometimes been caught off-guard by a simple misstep,such as choosing the wrong grade of materials in the manufacturing process.This is another area
39、 where vendors can help.“At WuXi Advanced Therapies,we have experience in supporting clients at all stages of development.With our global regulatory teams located in the US,China,and the UK,we are constantly monitoring the regulatory landscape and advise our clients proactively so that they can avoi
40、d any last-minute surprises when it comes to their submissions,”Cheung says.As an example of how regulatory demands can catch clients unaware,she cites the way the authorities have been in-creasingly asking for very detailed information on critical starting material like plasmid and packaging cell l
41、ines.“We have drug master files(DMFs)for our plasmids and our high-performing suspension cell line,which contains all the information clients would need for their investigational new drug(IND)or biological licence ap-plication(BLA)submission.”“Clients can simply refer-ence our DMF if they are submit
42、ting in the US,or our regulatory team can also prepare submission-ready documents for other coun-tries and regions like China and Europe.In the first half of 2022,our global regulatory team sup-ported clients with nine pre-IND,six IND and one BLA submissions.This shows how busy the field is,how busy
43、 we are and also our ability to be able to support clients,”she says.Industry AcceptanceThe concept of the CTDMO is new and as yet there are very few in existence.WuXi Advanced Therapies believes that it is the only one in the US,but others are emerging in the space.So,has the industry begun to get
44、to grips with the concept yet and to understand why integrated testing services are important?“Id say the industry is starting to get there,”says Stump.“Now people understand the need for testing and how important that is as part of the whole process.I still think theres some education“At WuXi Advan
45、ced Therapies,we have experience in supporting clients at all stages of development.”7/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)to do on our end as a whole about what that means and the benefits of it.But overall,the need is recognized in the industry.Its just figuring o
46、ut how to integrate that and who the players are in the field.”What is certainly not in doubt is the growth in the CGT space.Just 18 months ago,there were roughly 1,100 compounds in clinical development.Today,there are over 2,031 so the total has nearly doubled.2 It is certain,too,that the demand fo
47、r testing and manufacturing services will grow as these compounds move through the clinic.The forecast compound annual growth rate(CAGR)for cell and gene therapies is anything from 18.5%to 25.6%over the next five years.3,4,5Emergence Of A New Player The testing capabilities within WuXi Advanced Ther
48、apies go back three decades,although the company only came into its current form in 2017,when WuXi AppTec spun it out as a separate business unit comprising all of its manufacturing and testing operations in the US for advanced therapies.The unit brings together scientists from many different discip
49、lines.The testing capabilities within WuXi Advanced Therapies go back three decades.In 2017,WuXi AppTec set up its advanced therapies manufacturing and testing operations in the US as a separate business unit:WuXi Advanced Therapies.OXGENE was subsequently integrated into the business,which thus gai
50、ned a base in Europe for the first time.WuXi Advanced Therapies also added OXGENEs TESSA technology for adeno-associated viral(AAV)manufacturing and LentiVEX stable solutions for lentiviral manufacturing to its portfolio.TESSA has since been scaled up to 200L,achieving ten times higher yields and a
51、significantly higher percentage of full AAV capsids than plasmid-based methods.This could mean that more patients are treated from each bioreactor run compared to traditional plasmid-based systems,reducing raw material costs.In August 2022,WuXi Advanced Therapies announced an agreement under which i
52、t will license out the use of the TESSA technology to Janssen Biotech,a subsidiary of Johnson&Johnson.This will be a long-term relationship and Janssen will also have access to WuXi Advanced Therapies proprietary clonal suspension HEK293 cell line.The addition of OXGENE has been the largest single d
53、evelopment of the last two years,but WuXi Advanced Therapies also recently opened a new testing laboratory in Philadelphia,in the heart of the region that is becoming known as Cellicon Valley.The R400 building,named for its address at 400 Rouse Boulevard,is primarily focused on CGT testing to GMP st
54、andards.This both added capacity at least 2.0 to 2.5 times more than the previous LI-1 building and gave the company new capabilities in mycoplasma and sterility testing.8/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)References1.Citeline/WuXi AppTec Research Report,Streamlin
55、ing the CGT Manufacturing Process With Integrated Testing2.Q3 ASGCT Citeline Report|ASGCT American Society of Gene&Cell Therapy3.Drug Development April 2022:CELL&GENE THERAPY State of the Industry Where is C> Headed?(drug-)4.Global Newswire Facts&Factors:With 18.50%CAGR,Cell and Gene Therapy Consu
56、mables Market()5.Research&Markets:Cell and Gene Therapy Global Market Report 2022:By Product,By Application,By End-User()All in all,the pace of both growth and innovation in this sector is extraordinary.As Stump says,“I dont know many industries that could show an influx the way the CGT space is sho
57、wing right now.”That will create both an extraordinary opportunity for service providers in the field and also a challenge when it comes to growing pains and bottlenecks in terms of testing,development,and manufacturing.Integrating them in a single supplier could be the best way of exploiting the op
58、portunities and addressing the challenges.ConclusionThe CTDMO is a new concept in the pharmaceutical services sector and particularly in the CGT space.CGTs have outstanding potential but their growth is running ahead of manufacturing capacity and testing is a crucial element of the development proce
59、ss.Companies who can offer a fully integrated one-stop shop for testing as well as development,manufacturing and regulatory support have a big role to play.9/March 2023 Citeline UK Ltd 2023(Unauthorized photocopying prohibited.)About WuXi Advanced TherapiesWuXi Advanced Therapies is a global contrac
60、t testing,development and manufacturing organisation(CTDMO)headquartered in Philadelphia,USA,in the heart of the cell and gene therapy industry.It is the advanced therapies business unit of WuXi AppTec and provides innovative technology platforms for lentiviral and AAV plasmid,viral vector and cell
61、therapy manufacture and testing,accelerating time to market for cell and gene therapies.We are a comprehensive provider of viral vector and cell therapy testing for the advanced therapy industry,conducting testing for both therapeutics developers and other CDMOs.With OXGENE as our UK-based discovery
62、 engine,our in-house testing capabilities and significant manufacturing expertise combine to provide a fully integrated end-to-end solution for cell and gene therapy research,development,testing,and GMP manufacture that delivers a critical competitive advantage to our customers as we work together to cure faster and cure more.For more information,please visit https:/