March 15, 2006 (Vol. 26, No. 6)
Despite Contamination and Compliance Concerns, Flexibility Remains the Key Driver
Many CMOs across Europe are spreading their investment risk by building multiproduct manufacturing facilities. Such plants face issues that monoproduction ones dont, including the risk of cross contamination from the product mix in manufacture or left after change-over and cleaning processes, not to mention the constant addition of new customers and biotherapies to manufacture, diverse customer compliance expectations, and strict contractual commitments. So why are so many CMOs choosing this route?
Being a multiproduct site gives you the advantage of flexibility, as you never know with biotherapies which products will make it to market. This makes running a monoproduct plant risky. By running a multi-use plant, you are dividing the fixed costs of manufacturing, including the large outlay of paying employees among many different products, so it makes it run competitively. There is no idle capacity when marketing forecasts for manufacturing specific biotherapies are not met, says Friedrich Nachtmann, Ph.D., head of biotech cooperations at Sandoz (www.sandoz.com).
Sandoz is among the largest players in recombinant microbial manufacturing and an emerging force in mammalian cell culture. One of the most valuable lessons they have learned is how to run biomanufacturing facilities effectively.
Plant Design Is key
Staff in multiproduct CMOs agree that the risk of cross contamination is the biggest problem they face. According to companies that construct biomanufacturing facilities, such as NNE (www.nne.dk) and Pharmadule (www.pharmadule.com), before even starting work in a multiproduct facility, the design of the building has to be right.
Ulf Danielsson, vp of sales and marketing for Pharmadule, says, We have constructed facilities of 100200 m2 up to 15,00020,000 m2 for many biotech and pharma companies around the world, so we are experienced at what is needed for these buildings to meet regulatory requirements. With each client, we design and construct a customized building that meets their operational and product needs. However, we do use some basic principles that apply to most projects; for example, the room classifications need to be in accordance with the regulatory requirements.
Also there is often a need to have uni-directional material and personnel flows to prevent contamination, as well as interlocked doors in airlocks between cleanrooms. This prevents staff from opening both doors and exposing the cleanroom directly to an adjacent room or corridor. For biotech projects, the required biosafety level needs to be taken into consideration, and the air pressure between rooms needs to be designed properly to contain the active substances. In most designs, we also include windows in doors and walls so that staff can see inside the airlocks and suites to check who is in and what they are doing before they enter.
Derek Ellison, Ph.D., business development director of U.K.-based Eden Biodesign (www.edenbiodesign.com), a CMO that manufactures therapies from microbial and mammalian cells, as well as live virus for Phase I and Phase II studies, agrees with Danielsson. Because we recently built our facilities, the design was led by the technical team that will work in the suites rather than the structural engineers, says Dr. Ellison.
To do this, we took ten candidate biomanufacturing processes and used those to map out how we would use and clean the workspace, the material we would use, and waste flows we would generate each time. We then used all this information to provide input into how each suite should look. This is where we have a great advantage, as we havent had to adapt an existing building or had legacy equipment to try and fit into the process. We have been able to drive the design so our facilities match todays stringent quality regulations. We have knock-out panels in each suite so that we can easily move large equipment in and out to maintain future flexibility, adds Dr. Ellison.
Preventing Product Transfer
To prevent contamination from other products, most CMOs, especially the larger European ones, such as Girindus (www.girindus.com), Miltenyi Biotec (www.miltenyibiotec.com), Lonza (www.lonza.com), and Sandoz, use, where practical, closed systems that rely on automating as much of the process as possible and using fixed piping to prevent contamination from getting into the joints between systems and pipes.
Additionally, during a GMP campaign, CMOs that have a number of different production suites available only have one biotherapeutic at a time in each dedicated area.
At Medipolis, a microbial fermentation CMO in Finland that manufactures products mainly for Phase I and II trials, only one product will be in the 930-L fermenter area until this part of the production is finished.
However, since not all of the processes can be automated, the staff plays a key role in making sure products are kept apart. One important way to prevent contamination is to ensure staff turnover is low within the facility and that there is continuous GMP-training program in place. The quality of your processes relies on your people being experienced in what they are doing, comments Dr. Nachtmann.
Many companies also restrict the flow of personnel in and out of each area to prevent potential contamination from the different therapies in production. In our facilities we have a central corridor and an external corridor that runs around the suites, Dr. Ellison says, so that you cannot go from one to another without going out via the external corridor and then back through the change area into the central corridor again.
Some CMOs also prevent their personnel from having access to different production areas. According to Astrid Brammer, Ph.D., senior manger of business development at Strathmann Biotec (www.biotec-ag.de), a German microbial fermentation specialist that manufactures products for Phase I to III clinical trials and for commercial supply, Strathmanns facility has an airlock system with keypad codes so that staff from the fermentation area cannot enter the chromatography suite because they do not have the authorization codes to do so.
During production in multiproduct CMOs, even clothing comes under suspicion of harboring contaminants. We have dedicated color-coded gowns for the different production suites (for example, fermentation, purification, and so on) because even though gowns are washed regularly, there is still a chance that they could carry something unwanted from one suite to another so we make sure they are kept separate, Sirkka Aho, CTO of Medipolis explains.
During product changeover in a multiproduct facility, such as Boehringer Ingelheim (www.boehringer-ingelheim.com), one of Europes largest CMOs producing Phase IIII biopharmaceuticals and commercial therapies from microbial and mammalian cells, a rigorous cleaning process is carried out using chemicals including phosphoric acid and sodium hydroxide. Systems are either cleaned in place, or in the smaller CMOs staff can move them out of the production suites for cleaning.
After cleaning, equipment is rinsed and swabbed to test it for residues and analyzed for total organic carbon and nucleic acids, as well as microbial contaminants such as bioburden and endotoxins.
To check that the residue amounts present are not above the defined acceptance levels after the cross-over phase, cleaning validation and recovery studies are of key importance. We are mindful of contamination and even do cleaning and recovery studies on the systems we use for small-scale pilot work in order to collect information before we continue into GMP manufacturing. We also use dedicated equipment wherever possible because we view any contamination risk seriously, says Monika Henninger, Ph.D., head of customer relations and client projects at Boehringer Ingelheim.
Liselotte Larsson, Ph.D, marketing manager of Novozymes Biopharma (www.novozymes.com), a niche CMO based in Sweden that specializes in microbial fermentation to provide therapies for Phase I and II trials as well as some commercial products says, The main difference for a multiproduct manufacturing facility is that not only do you have more rigorous cleaning procedures but you have to document and prove that everything is clean too.
Where practical, we are now using disposable equipment in our processes as this means we have less cleaning and cleaning validation to do. There is a growing trend in many multiproduct CMOs toward the use of disposables.
In addition to using disposables, we also prevent cross contamination by using dedicated materials like hoses, membranes, filters, and chromatographic resins for each product, says Aho.
Other challenges that face multiproduct facilities are the constant addition of new clients and therapies, along with the diverse compliance expectations and contractual commitments they bring. Many CMOs do not see these additions as large an obstacle to their business as preventing cross-contamination because being able to scale up manufacturing and purify a range of different biological molecules according to strict timelines and regulations is their core expertise. Many CMOs can also often modify their standard manufacturing processes to fit their clients needs whereas any cleaning procedures that CMOs use may have to be customized for the product.
Being a successful CMO is all about good communication. We put in place quality agreements and project-management teams internally and in the client company at the beginning of work so that both parties have to take responsibility for time lines and costs. This way we can all manage our expectations of how the project is progressing, says Dr. Henninger.
Another issue that multiproduct manufacturers face, which is not often touched upon, is confidentiality. In this type of environment it is critical that you protect the identity of your clients biotherapy, and we do this by giving products codes so that only those working on the project are aware of what they are manufacturing. We also do not have external visitors to the plant when a therapeutic is at a crucial stage of production, says Dr. Henninger.
Feeling the Pinch
The market for biomanufacturing is still growing in Europe because biotechs are maturing here, and the mid-sized biotechs are now looking for manufacturing facilities. The big pharmas dont want to block their plants with small-scale production runs for smaller campaigns so CMOs are able to fill that gap very well in Europe, says Dr. Brammer.
However, as Dr. Larsson explains, For a CMO to make money, it is still a fine balancing act. We need the business from biotechs, and if the funding situation across Europe and Scandinavia does not improve, many will not have the cash to outsource their production to us, so the market will contract in size. Also, with the increasing number of CMOs setting up in India and South East Asia, CMOs in Europe and Scandinavia will continually need to find ways of staying competitively priced.
If you build and run a multiproduct facility, then there is much less chance of wasting time and money as there are several cases in the biotech and pharma industry where we have constructed single-use sites only to see them sit idle because the product did not become as successful, or worse, did not obtain regulatory approval. By running a multiproduct plant you are less likely to be left with this type of white elephant, and with our modular buildings, the smaller ones could even be shipped to a different location to meet a capacity crunch elsewhere, says Danielsson.
Recent history of the pharma industry shows that facilities originally set up to manufacture one product need major reconstruction work for multiproduct manufacturing. It saves a lot of money and reduces risk to set up your plant as a multiproduct unit to begin with.
Being fast and flexible are the best ways to become a successful CMO in Europe, and despite the challenges working in a multiproduct facility present, you have no choice but to run this type of manufacturing to achieve that in todays market, agrees Dr. Nachtmann.