The pharma industry is still heavily reliant on stainless steel. How are manufacturers integrating stainless steel and single-use
components and what impact does this have on sterile environments?
In existing facilities, it is common for biopharmaceutical manufacturers to develop a “hybrid” system of both existing stainless
steel and new single-use components. In build-outs or new facilities, particularly at small to moderate scale, more single-use
is being introduced. At the larger scale, hybrid systems again dominate with large fermenters, chromatography columns and
tangential flow filtration (TFF) systems continuing in stainless steel, while buffer and intermediate/final product hold tanks
and filters are introduced as single-use systems. These hybrid systems will be used in large volume production facilities
for quite some time, particularly in the downstream area despite progress made in operation technologies such as single-use
TFF. Most biosimilar production today is focused on large volume drugs where stainless steel will still predominate, especially
for large bioreactors and chromatography columns. In filling areas, however, we are seeing a lot of interest in single-use
formulation and filling systems, but we have to take into account the large installation base of stainless steel filling equipment.
Functionally, manufacturers integrate stainless steel and single-use components or systems using linking technologies that
are typically steam sterilisable (“steam-to” or “steam-through” connectors). The linking technology is steamed with the stainless
portion of the process. Then the single-use flow path (which is typically pre-sterilised by autoclave or gamma irradiation)
is opened to the stainless portion.
What are the current hurdles to the increased use of single-use systems in aseptic environments? What is the regulatory perspective?
Regulatory requirements are spelled out in existing GMP documents: process equipment and bulk drug product containers must
not adversely affect final drug product quality or safety. Drug manufacturers must demonstrate that single-use systems used
in aseptic environments do not introduce leachables, particles or microbes to the drug product that could compromise the product
or patient safety. Hurdles include understanding how supplier extractables data, when suitable, can be applied to assess potential
toxicity of leachables, while minimizing or even eliminating the need for additional testing, and how and when additional
leachables testing should be applied. Drug manufacturers also need to better understand how to apply extractables and leachables
data in the context of final dosage levels and understand potential toxicological impact (or, more commonly, substantiate
the absence of toxicity above established safety threshold levels). Microbial safety (i.e., sterility) is ensured by validated
sterilisation using gamma irradiation, but drug manufacturers need to know what supplier documentation must be submitted to
regulatory agencies and understand how the valid sterilized state is maintained for each batch of single-use equipment. Particles
from single use systems are generally controlled by in-line filters, but in final filling manifolds and aseptic systems without
sterilizing filters, control of particles by the component and assembled system supplier, as well as implementation of flushing
protocols where appropriate, must be considered. Another potential hurdle is understanding how to flush and perform integrity
tests on in-line sterile filters prior to use when required. Lastly, as there is currently no test to ensure the leak or microbial
barrier integrity of assembled single-use systems, components and assembly must be designed and controlled to minimize risk
of leaks, and users must learn to trust these assurances in the absence of an on-site pre-use system integrity test correlated
to microbial barrier performance. These are key areas where drug manufacturers must work with their supplier partners to design
single-use systems and operating procedures that facilitate appropriate use and meet quality and safety requirements.