Biomedical Engineering Reference
In-Depth Information
9
Filling and
Finishing Systems
I never see what has been done; I only see what remains to be done.
Buddha
There are two stages where a biological product requires filling in contain-
ers for long-term storage. First, it comes at the end of the downstream cycle
when a purified solution of a protein drug is ready to be filled into containers
as a bulk drug that will be shipped out to companies to formulate and finish
the product in a dosage form for the end customer. The second stage of filling
is to formulate the bulk and fill into end-customer dosage form, a syringe,
vial, or ampoule.
The bulk product is generally labeled as a pharmacopoeia product, such
as “Erythropoietin Concentrated Solution EP,” and would thus comply with
all requirements of labeling as required in the pharmacopoeia. There is no
need for any formulation additives, and the last buffer exchange in the down-
stream processing likely already brought it into a formulation that is stable.
This stage of filling is conducted as a continuation of downstream process-
ing. Sterile serum bottles are available for packaging the product (e.g., from
Thomas Scientific,
www.thomassci.com
) in sizes from 25 mL to 9 L. These
solutions can alternately be filled in sterile flexible bags. It would be prudent to
fill them using a sterile filter as the final stage, perhaps a virus-clearing filter.
The second stage of filling protein solutions is more demanding. The final
production step is transferring the new medium from the transfer vessel
or bags and into vials for distribution. Traditionally, the final fill operation
consisted of stainless steel equipment connected via reusable valves, rigid
tubing, and steel pipes. Again, this equipment requires validation and must
be subjected to a cleaning-in-place (CIP) cycle after each filling cycle is com-
pleted. Today, many process engineers are designing this operation with
single-use tubing assemblies in place of stainless steel piping to reduce ster-
ilization time and cost.
One example of integrating single-use systems in a final fill operation is
for simplifying mobile transfer tanks. These tanks with disposable liners
are designed to transfer a product from formulation suites to storage areas
and ultimately to filling suites. To allow sterile connection to and from these
vessels, designers traditionally add three-way valve assemblies to fill and
drain ports to facilitate sterilization-in-place (SIP) operations. The design of
these three-way valves makes it difficult to validate cleaning procedures.
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