1. Special Report: Disposables
At the End of the Line: Single-Use
Technologies in Fill-Finish Operations
Amy Ritter
T
he surge in the number of biologics natural transition from bench-top to large-
The incorporation in the drug-development pipeline, scale cell culture, and have evolved in size
of single-use over 900 according to the latest
report from the Pharmaceutical Manu-
and complexity to fit the special needs of
manufacturing-scale operations. Dispos-
components in facturers Association, introduces pressure able downstream-processing tools have
on manufacturers to handle increasing also been adapted to meet the demands of
the fill-finish line numbers of small-volume products (1). In large-scale bioprocessing. At the very end
provides increased fill-finish operations, this means manu-
facturers must have the ability to quickly
of the biomanufacturing line is the fill-fin-
ish operation, where single-use technolo-
flexibility to and efficiently switch their fill line from gies are just beginning to make inroads.
product to product without compromising Fill-finish is the last step in the man-
multi-product product quality or sterility. Manufactur- ufacturing operation, after which the
manufacturers. ers are beginning to take advantage of the
benefits afforded by single-use technolo-
product is passed to the patient. As
such, product quality and the possibility
Image: Influx productIons, photodIsk, getty Images
gies to address these needs. of contamination are of special concern
Single-use technologies are now when a manufacturer is considering
widely-accepted tools in drug manufac- whether to implement single-use tech-
turing, particularly manufacturing of bio- nologies. The fill occurs downstream of
logics. A recent biomanufacturing survey the last filtration step, so there is a height-
in Pharmaceutical Technology indicated ened sensitivity to sterility risks and the
that 66% of respondents use at least some introduction of particulates. As with all
disposable components in their manufac- disposable applications, product/mate-
turing operations, and an additional 9% rial interactions and extractables and
of respondents indicated that they use all leachables are also a concern.
disposables (2). Disposable upstream- In some cases, manufacturers may be
processing tools, such as bioreactors and reluctant to switch to a disposable line
media storage containers have made a from a well-validated stainless-steel fill
2 Pharmaceutical Technology OctOber 2011 P h a r mTe c h . c o m

2. Special Report: Disposables
line, where process engineers have exten- tant factor in the decision to implement its simplest, a filling line can consist of
sive experience in cleaning and validat- a single-use fill line. “Market pressure a product container bag, a pump and a
ing the system and are confident in their and good business sense dictate that we filling needle, all connected by plastic
quality control operation. Kent Payne, need to use our filling assets for manu- tubing. Disposable filling lines, suitable
vice-president and general manager, facturing product, not for getting ready for smaller-scale fills are available as
Development Services, Catalent Pharma to manufacture product. The need to get “plug-and-play” systems, where the line
Solutions indicated that in general, a big the most product out of the process is in- comes fully assembled and presterilized,
obstacle to adopting single-use technolo- creasingly critical to the business. That ready to be used, and needing only to be
gies in other parts of the manufacturing said, the paradigm of a few blockbuster attached to a peristaltic pump. Such sys-
process has been a reluctance to change. vaccines allowing for long campaign tems are adequate for small-scale fills, but
“The biggest challenge we faced in ap- operation and few product-to-product do not operate at high speed and may not
plying single use systems elsewhere was changeovers is under pressure as prod- be suitable for high-viscosity products.
changing mindset to be open to new ap- ucts portfolios become more focused on Pump technology has improved to the
proaches from what we were used to,” he multiple (lower annual volume) biolog- point where disposable filling lines are
says. For single-use systems, validation of ics. This means that a production facility feasible, but further improvements are
sterility and integrity is done by the sup- is faced with the challenge of more fre- possible. Peristaltic pumps have only re-
plier of the components, rather than the quently changing the facility and equip- cently achieved the accuracy required for
manufacturer. Handing these important ment over to process different products. fill applications. They are still limited by
quality checks over to another party re- The reduction of changeover time has speed, and the tubing that runs through
quires a leap of faith that some may not therefore become one of the primary the pump is subject to degradation and de-
be comfortable making. influences in our decision to implement formation over time. Plastic, disposable,
On the other hand, single-use tech- single-use technology for current fill- rolling-diaphragm pumps are currently
nologies, offer advantages over stainless ing facilities.” Indeed, Beyeler reported available and offer an alternative. How-
systems in control of contamination. a reduction in changeover time from 16 ever, more rigorous applications, where
In the PharmTech survey, a majority of hours to two hours when switching to a high-volume, high-speed, or high-pressure
respondents, listed reduced risk of con- single-use line. In addition, a recent re- are required, may be places where stainless
tamination as an advantage to single use port produced by authors from Millipore steel continues to be the better choice.
systems (2). A single-use filling line can demonstrated a similar reduction in total There is plenty of room for new tech-
be configured to have fewer connection processing time, from 19 hours to 1.5 nology to adapt to these challenges. Beye-
points than a fixed-pipe line, thus reduc- hours, when switching from a stainless ler says “At the moment, I think what has
ing the risk of microbial contamination. system to a single-use system (3). been offered is that which is the easiest
Moreover, since the line is only used for On average, biotech companies out- and least risky to develop from the equip-
a single product, there is no risk of carry- source 81% of their fill-and-finish require- ment vendors, a single-use version of what
over contamination. Althea Technologies ments. Biotechnology and pharmaceuti- is already on the market. Some equipment
uses disposable technologies in all of its cal companies with in-house capabilities suppliers for upstream processing have in-
fill operations. According to Chris Duffy, outsource 40% of their requirements (4). novated beyond the “also in single-use”
vice-president of operations, “Preventing This means that CMOs are handling a type of approach and have developed
cross-contamination is an issue that Al- large variety of filling operations, and specifically new technologies. As vendors
thea takes very seriously. To ensure that can benefit from the flexibility afforded increasingly see the potential competitive
there is no carryover from project to proj- by single-use systems to handle multiple advantages for single-use technologies I
ect, Althea has stringent changeover pro- products. Althea’s Duffy notes, “Stainless am looking for them to specifically invest
cedures and operates its fill facility with equipment requirements vary from client R&D in developing innovative filling
disposable technology in virtually 100% to client. When not in use, these must be technologies.“ The requirements for speed
of our fill operations, from small-scale stored and when they are placed back into and cost-effectiveness in multiproduct
phase I clinical supplies to commercial service must be cleaned again.” The ability manufacturing will drive the develop-
manufacturing.” to quickly reconfigure the line to accom- ment of new disposable technologies for
modate different size runs, different bio- fill-finish operations.
Time savings and flexibility safety requirements, or different product
Perhaps the biggest benefit to be gained containers (e.g., vials versus syringes) adds References
by implementing a single-use filling line greater flexibility to the filling operation. 1. Biotechnology Medicines in Development.
is the savings in time gained by eliminat- PhRMA (September, 2011).
2. M. Hoffman, Pharm. Tech. 35(5), s6 (2011).
ing the cleaning and validation steps. Na- Evolving equipment requirements 3. E. Jenness and V. Gupta, BioProcess Int.
than Beyeler, process engineer at Merck It is often the case that equipment evolves 9(s2), 22–25 (2011).
Sharp and Dohme, cited the decrease to fill an unmet need, and this is the 4. J. Hartingan and W. Downey, GEN 31(10),
in changeover time as being an impor- case with disposables for fill-finish. At (2011). PT
4 Pharmaceutical Technology OctOber 2011 P h a r mTe c h . c o m