Once the single-use supply chain has been established, it is crucial to assess what qualification activities are needed to
implement a single-use system. While it is common knowledge that leachable-and-extractables testing is a necessary part of
a single-use component program, it's important to realize that leachable-and-extractables testing can be costly to perform.
However, testing may be reduced depending on the overall risk to the product for each single-use item. According to Destry
M. Sillivan of FDA, manufacturers should "submit sufficient information to provide evidence that the product contacting material
does not introduce contaminants into the product so as to alter the safety, identity, strength, etc." (5). If there is little
to no relevant risk associated with the material in question, "vendor data can be cross referenced and a detailed justification
for the applicability of these data and a justification for no additional testing should be submitted" (5).
When assessing what qualification activities are needed for single-use component implementation, it is important to identify
the product contact components that may present a higher leachable and extractable risk. A risk assessment is a valuable tool
to determine what the crucial single-use materials are in a process. Those that surpass the tolerable amount of risk for an
organization may then be slated for acquiring additional vendor information and further in-house testing. Multiple factors
should be considered as part of the risk assessment including the nature of final product, how the process stream contacts
the single-use component, the single-use component material properties, and the attributes of the process solvents. Once appropriate
risk factors have been identified, a risk assessment should then be used to determine the extent of the qualification required
for each component. Tools for performing a risk assessment as well as the general risk-based philosophy are outlined in ICH,
Q9 Quality Risk Management (6).
It is important to recognize that a single-use item is often composed of many component parts that may or may not be made
out of the same materials. Vendor documentation should be closely inspected to determine the material of construction of each
component. Not all of these component parts may be manufactured at the vendor's facility. A primary reason for this is that
many vendors outsource different components that comprise their single-use assemblies. Accordingly, subvendors must be contacted
to obtain their validation packages for the individual parts to complete the risk assessment.
Consider, for example, a single-use bag system; there are the bag films, the connectors, the tubing, the capsule filters,
and sampling connections as shown in Figure 3. As noted above, each of these items may be made out of different materials that all need to be considered for potential risk
Figure 3: Single-use storage bag example risk assessment.
This example of a risk assessment performed on a storage bag illustrates how different components of a single-use bag can
have different risk scores. The storage bag itself is rated at a higher risk relative to the rest of the component parts because
it has a larger surface-area-to-volume ratio and the film is in contact with the storage material for an extended period of
time. Where this bag is used in the production process will determine the overall outcome of the risk assessment. If the storage
bag was used in upstream process the risk is low; however, if the storage bag was used in late stages of the process it becomes
a much higher risk and would require leachable testing.
What the drug product is intended to treat, the intended route of administration, and where the single-use item is used within
the process stream are the leading risk factors. The longer the product is in contact with the single-use item, the greater
the risk that leachables will be transferred into the process stream. When considering this risk factor, it is important to
recognize that the tubing on a component part may only see the process stream for a fraction of the time that a bag may see.
This and the varying materials of construction are the reasons that component parts of each assembly should be considered
separately. The proximity of the single-use item to final fill will increase the risk because there is less opportunity for
the leachable (or particulate) to be mechanically or chemically removed via filtration or chromatography. The volume of product
stream when compared with the surface area of the single-use item is also an important risk factor because the lower the volume
is, the more potentially leaching surface area that it may contact. Consider the product contact area of a ultrafiltration/diafiltration
(UF/DF) filter; the exceptionally high surface area as well as its proximity to the end of the process makes it a much higher
risk to the product than an upstream storage bag.