Morten Munk is Vice President, Business Development, CMC Biologics A/S.

Morten Munk

This article is part of a special feature on single-use systems that was published in the October issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1010.

The benefits that can be gained by integrating single-use systems into a commercial cell culture facility depend on whether the systems are to be used in an existing or a new facility. It is usually more beneficial to use Single-use systems in a new facility because this offers the opportunity to reduce the requirements for floor space and to reduce or eliminate the need for utilities, such as steam, ventilation, cleaninplace systems, water systems, etc. 

Single-use systems can be used in both upstream and downstream manufacturing. In general, the greater the use of such systems in a facility, the better the cost saving will be, with full single-use system implementation being the most optimal solution. Single-use systems also make it easier to establish a contained production facility, which enables manufacturing to be conducted in a truly closed process environment. 

Currently available single-use cell culture reactors are currently limited to a size of 2000 L; however, it is possible to install several Single-use systems in ranges from 1000 L to 2000 L in the same facility. Making space for 12 docking stations for a Single-use reactor will offer the flexibility to manufacture from 1000 L to 24000 L in the same facility. The implementation is even more advantageous if the facility is to be used for several products. 

The benefits and challenges of single-use systems

There are many benefits to using single-use systems for cell culture 

Lower initial investment for single-use systems both for the facility and for the equipment (cell culture reactors, etc.).

Shorter time to establish a facility. This allows the sponsor to delay the building of a dedicated facility until later in the product development phases, therefore providing peace of mind if the product fails clinical testing or if there are any concerns regarding the amount of product that is required to serve the market. It also gives the manufacturer more time to gain greater knowledge about the manufacturing process. 

shows the advantages of having the option to postpone the building of a new facility for a specific product.

Less cost and time for validation/qualification.

Less downtime in the facility for cleaning and elimination of cleaning verification.

Reduced depreciation of capital expenditure.

Reduced environmental impact with reduced energy requirements and lower CO

 emissions. Thus, companies will be better prepared for future requirements for green technology or sustainability initiatives.

Higher flexibility for accommodating market variations during the lifecycle of a product.

Higher flexibility for changing between products on a campaign basis or changing a dedicated facility to a new product.

Reduced impact of facility failure, such as breakdown of a critical piece of equipment, contamination of production equipment or a major disaster, such as fire. 

Despite the advantages of single-use systems, however, there are a few challenges to incorporating them into cell culture production facilities. One important factor is the manufacturer's dependency on the vendor — if the vendors do not supply the single-use systems as required then production may have to cease. Additionally, there is a dependency on the vendor's quality systems. These vendor issues can, to some extent, be mitigated by working very closely with vendors, including performing frequent vendor audits. A centralised vendor control agency would be a large advantage, but this is not likely to happen in the near future. However, it may be that an organisation such as the ISO may eventually initiate such an audit programme.  

Technical limitations; for example, high pressure, a high requirement for removal of heat or requirements for vigorous agitation, e.g., large-scale microbial fermentations.

The size of the operation and difficulties in handling large volumes.

Reuse of very expensive materials, such as chromatographic resins. Such issues can, to some extent, be mitigated using the single-use system for several batches; however, single-use system reuse or campaigning is very controversial since the whole idea of single-use systems is, as the name suggests, that the system is only used once. If you pack a column with 100 L of Protein A resin costing €10000 per L, however, then you will not throw this column away after using it once. To make the downstream process economically feasible for single-use systems, a solution is needed that enables a single-use column to be used several times. One way is to define 'one use' as for as long as the column is not repacked. It might also be possible to define a rise process, which is different to the cleaning process and which is acceptable between sublots. It could be argued that as long as the system is not cleaned, it is only being used once. Another solution is to accept that a single-use system component can be used several times if a risk-based justification is included in the process design and is documented to the authorities. In all cases, system reuse should always be carefully considered before implementation.

Issues concerning extractables and leachables. This issue has been exaggerated to some extent as the potential risk from a single-use system in API manufacturing is minimal compared with the potential risk of the infusion bag or tubing used in final drug delivery to the patient.

Reliable product contact process parameter monitors (pH, O

, product concentration probes, etc.) must be used.

One of the most predominant challenges, however, is the perception and conservatism of single-use systems from the authorities, as well as from manufacturers who have already invested heavily in conventional systems. This can only be overcome by information and support, and a willingness to implement single-use systems.  

Manufacturing conducted with Single-use systems produces more solid waste than traditional stainless steel manufacturing equipment. However, the waste from a facility using Single-use systems can be treated in the same manner as the waste generated by hospitals. The processes for handling and disposing of hospital waste are simple, straightforward and well established, so there shouldn't be any additional expenses or regulatory burdens in disposing of single-use systems manufacturing waste. Minimising waste and increasing the recycling of material should always be part of the considerations when developing a Single-use system. One important parameter in this aspect is for the vendors to make it as easy as possible after a decontamination to separate the Single-use system into individual components (metal, electronics and different types of polymers). 

To improve commercial cell culture manufacturing, the cost effectiveness of the downstream components of the manufacturing process has to be increased. This could perhaps be achieved through careful system reuse or finding a new way of performing purification without the need for very expensive chromatographic resins. The main problem is that the cost associated with currently available single-use systems is far too high.  

Other areas that will be interesting to keep an eye on are:  

Avoiding the open handling of the initial seeding with a 1 mL working cell bank by developing systems where the initial seed is frozen in a 100 mL bag which can be connected to the seed reactor. This will make upstream operation a truly closed process. 

Developing a large-scale disposable low-shear pump. At the moment, peristaltic pumps are pretty much the only type of pumps that are single use. Peristaltic pumps have several disadvantages, including the risk of the pump cutting up the tube, limitations in pressure and the demand for high maintenance, which is the reason for their limited use outside of the single-use area.

Integrating flow sensors and pressure sensors into disposable purification systems.

Developing integrated systems that cut down on tubing length. 

The author would like to thank David Wolton at CMC Biologics for his kind assistance with this article. 

is Vice President, Business Development, CMC Biologics A/S. 

Articles

The benefits that can be gained by integrating single-use systems into a commercial cell culture facility depend on whether the systems are to be used in an existing or a new facility. It is usually more beneficial to use Single-use systems in a new facility because this offers the opportunity to reduce the requirements for floor space and to reduce or eliminate the need for utilities, such as steam, ventilation, cleaninplace systems, water systems, etc.