Aseptic compounding and processing
Mathew Cherian, PhD, director of One 2 One Global Pharmaceutical Services at Hospira.
Figure 1: (aseptic compounding): An example of an aseptic manufacturing line. (COURTESY OF HOSPIRA)
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Traditional sterile processing entails compounding in a Class C environment, followed by various process steps, culminating
in sterile filtration into a Class A environment for filling. Aseptic compounding and processing offer an alternative to the
traditional modality when processing highly potent and toxic sterile pharmaceutical products. Aseptic compounding and processing
use an equipment train that has been precleaned, connected, hermetically sealed, and sterilized. The entire process is carried
out under aseptic conditions. The active principle and excipient(s) are sterile-filtered in suitable solvents. Various process
streams may be mixed, including solvent removal, solid-dispersions formation, homogenization, and finally the product filling
(see Figure 1 [aseptic compounding]).
Aseptic compounding offers the advantage of being able to manufacture sterile products under the cleanest conditions used
in the industry. By virtue of sterile filtration into a previously sterilized equipment train, the bioburden is extremely
low, and particulate contamination attributed to environment and starting materials are obviated. In addition, no final filtration
is necessary. For large-volume parenterals that are required to be terminally sterilized under US regulations, a lower F0
value, a measure of heat input, may be justified (1). This condition is especially helpful if the product is thermolabile.
Manufacturing considerations.
Safe use of solvents for various process steps is helped by the hermetically sealed equipment train. Use of flammable and
toxic solvents is made possible, including Class C solvents. There is no need to have explosion-proof facilities when handling
flammable solvents, such as ethanol. Downstream steps, such as sparging or diafiltration, can be used to remove the solvents
to the required level. If dry equipment is needed at one or more stages of the processing, dryness is easily achieved poststerilization
by passing sterile filtered air through the equipment while the equipment is still hot. The equipment typically used for aseptic
compounding makes it possible to have precise temperature control over the entire process. It also is possible to extend the
processing time, when needed, as there is no risk of increased bioburden due to protracted holding and processing time.
Highly potent compounds increasingly are used in the pharmaceutical industry. These compounds may be hormones, cytotoxics,
or certain biopharmaceuticals. Aseptic compounding and processing is the safest way to handle these compounds. If oxygen sensitivity
of the active principle is of concern, aseptic processing offers a safeguard against oxidative damage during processing since
inert gases, such as nitrogen, are safe and easy to use.
Aseptic compounding, however, presents its own challenges. The equipment train is more expensive, and generally speaking,
the cleaning process can be more complex. All surfaces, valves, pumps, temperature, and pressure gauges need to be of sanitary
design because of the high level of cleanliness required. Cleaning validation is more challenging because it may sometimes
be difficult to determine the source of contamination in a long equipment train.
Typically, clean-in-place (CIP) and steam-in-place (SIP) techniques are used. SIP of long equipment trains can be difficult
as condensing steam may not reach the entire length of the equipment. Multiple steam entry points may be required. If the
process train involves a high pressure homogenizer, an artificial negative for bacterial presence is possible. Media runs
are required to validate the aseptic state of the process.
In summary, aseptic compounding and processing are an effective processing method for highly potent and toxic sterile pharmaceutical
products, especially when solvents are used in preparing them. No final filtration is necessary, the drug can be protected
from oxidation, and it is possible to achieve greater flexibility in process parameters, such as temperature and holding time.
Reference
1. FDA, Guidance for the Industry: Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice (Rockville, MD, Sept. 2004).
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