Disposables in Bioprocessing
by the Disposables Community of Practice (COP)
*Editor’s Note: This article provides highlights from the discussion on disposables in the draft
ISPE Guide: Biopharmaceutical Process Development and Manufacturing, currently under
development.
Upstream
Disposable technology is starting to have a significant impact in upstream Mammalian cell culture. It is
now possible to have completely disposable manufacture from out of freeze to the start of
chromatography at the 2000L disposable bioreactor scale. This makes the technology no longer limited
to the lab, but brings it into main stream manufacture.
Recent implementation has also shown that production suites that were originally designed for a 100L
SS reactor can be retrofitted with a 2000L disposable reactor and its associated seed train.
(See inset photo.)
Mammalian Cell Culture
The impact of this is that current
factories can now produce far more
product than they can possibly purify.
How this can be delt with is covered in
the purification section.
Another impact of this technology is
that more complex processes like
perfusion, concentrated fed batch,
contained TFF, and disposable
centrifugation become easier to design,
implement, and use. Because of the
simplicity of the irradiated systems and
the advent of disposable flow meters
/pressure sensors, these complicated
systems can be assembled and made
operational in a matter of hours.
This gives much more flexability to the Development department to make the most efficent process that
suits the product. There have been examples where these complicated Development systems have been
designed, made, irradiated, and delivered within three weeks.
Microbial Cell Culture
Microbial manufacture presents many more challenges than mammalian in regards to disposables.
However, this makes it attractive for disposables manufacturers that want to service a completely unmet
need. It is therefore probable that disposables will soon be competing in this area.
Downstream
The Downstream area has been using large amounts of disposables for some time now, especially for
buffer storage. Recent advances in disposable sensors and equipment mean that more of the main
process equipment can be retrofitted with disposable versions (Columns, TFF, Filter sets etc). The main
issue that faces the industry is that with the advent of the 2000L bioreactor, the Downstream area is
struggling to keep pace. This mainly revolves around the increase in amount of buffer needed and
advances needed in how buffer areas are designed and how/where the buffer is stored. From an
operational perspective, the nearer the buffer is made/stored to the process, the more efficent the
process will be.
Process Support and Utilities
Single use technologies usually represent a simplification of process support and utilities. The technology
does not impose special requirements on clean utility systems (gases, water, clean steam, cleaning
fluids), as the main impact is reduction, if not elimination of cleaning and sterilization systems.
The potential for single use technology should be investigated when designing a process, since reductions
in scope and capacity of process support and utilities will improve both project cost and timelines.
Generation and distribution for the following process support systems and utilities may be reduced:
ƒ
Purified water
ƒ
Water for Injection (WFI)
ƒ
Clean steam
ƒ
CIP
It is possible to entirely avoid installation of clean steam and CIP-systems for some processes depending
on the process steps involved. If supply of readymade media, buffers, and WFI in mobile single use bags
are added, further elimination of also the water systems become possible.
Impact on process support systems for inactivation of solid waste from single use processes should be
evaluated. Depending on the application, these installations should be considered:
ƒ
Inactivation autoclave
ƒ
Chemical inactivation fluid preparation
ƒ
Chemical inactivation waste collection and neutralization
The inactivation autoclave offers handling free from hazardopus materials, but requires steam
generation, distribution, and condensate drain to waste. Provisions for safe draining of single use systems
to waste should be made available regardless of inactivation strategy.
Bins and dollies for mobile single use bags may still have to be cleaned manually, so a suitable area for
cleaning and wipedown should be considered.
An interface between plastic and steel systems represent a special area of concern because the weaker
plastic system may be subject to relatively high temperatures and pressures should the interface barrier
fail under cleaning and sterilization conditions.
Facilities
Type and extent of single use technology foreseen for the process should be addressed for optimal
arrangement of the facility. Single use technology shifts some focus over to manual operations for setup
and transportation, so these activities should be reflected in the facility design as they can impact
productivity and success rates.
Stainless steel systems can be designed to reinstate the closed state after opening by cleaning and
steaming in place, and integrity can be demonstrated by various test methods – so lesser degrees of
suite cleanliness classifications can be appropriate. Single use systems do not need to be opened for
cleaning, but are difficult to test for integrity and connection operations are manual. Opening the process
for connection can be avoided by use of tube welders or single use aseptic connection devices.
Specific attention should be given to the background cleanliness classification for process steps where
connections are made or the process is opened. There may be an advantage in going up in cleanliness
classification to gain some flexibility in connection methods as opposed to cumbersome operations for
safe connections in a lower cleanliness classification.
Single use systems are sensitive to correct installation and loss of integrity can impact product quality, so
there must be sufficient space for operator access for careful and potentially supervised installation. Area
considerations directly related to single use systems are:
ƒ
Ceiling height (setup, agitator introduction, charging)
ƒ
Area for ladder for setting up or charging to tall systems
ƒ
Area for operation of pallet lifter
ƒ
Corridor and door width to facilitate safe transport
Potential for reduction or elimination of process support and utilities as discussed in the preceeding
paragraph can impact favorably on area need for generation and distribution of liquids and steam, but
the technology may also require additional areas for:
ƒ
Storage and assembly of systems
ƒ
Transportation and storage of mobile bags
ƒ
Cleaning and parking of bins or dollies
ƒ
Storage of solid waste
Stacking bins two or three up can deliver a good volume to footprint ratio even when space for the lifting
device is included.
Since single use technology can change the distribution philosphy from hardpiped flow to manual
transportation of liquids in mobile bags, transportation distances between preparation, storage,
application, and parking areas should be minimized. Facility design should consider what bags absolutely
need to be transported into the process suite and what bags can just be placed in the outside corridor
and hooked up to process systems through penetrations in the process suite wall.
Through-the-wall or through-the-floor distribution of single use tubing for connections of process steps or
supply of liquids should be supported by engineering efforts to mitigate the risk of erroneous connections.
Examples of facility related controls are:
ƒ
Color coding
ƒ
Physical arrangement
ƒ
Transparency for visual checks and communication
Solid waste from single use systems is generated in cycle following the batch and process support
systems cycles and so may be generated with uneven frequencies. The facility should have storage areas
for collected solid waste. It may be necessary to include areas for draining and inactivation of the waste.
Smaller volumes can be collected in biohazard bags, put into controlled area storage, and inactivated by
incineration off site.
Upcoming ISPE Document for Single Use Technology
One of the main future activities for ISPE’s Disposables community will be to support the drafting and
publishing of an upcoming ISPE document on Single Use Technology. We aim to have a draft outline
ready in 2011, the draft document out for industry review in first half of 2012, and the final document
approved and published in the second half year of 2012. The writing effort is coordinated with the ISPE
Guide: Biopharmaceutical Process Development and Manufacturing task team. This collaborative effort is
open for all ISPE-members and the Disposables COP steering committee encourages input from as many
perspectives as possible. Please consider contributing your input for this disposables-focused document
and watch for updates on progress and invitations to join the team of writers and/or reviewers.