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Closed system Filling Technology: A New Paradigm
Article · November 2015
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David Hussong
Concordia ValSource, LLC
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“Closed system filling” is a new set of
processing controls appropriate for a
sterile filling process that eliminates potential microbiological contamination
from environmental and operator sources through the use of closed systems.
This is an automated sterile connector
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containers are filled through an engineered and controlled passage enabling
the filled product, the internal container
and the closure system surfaces to avoid
exposure to the background environment. When using this manufacturing
technology, the sterile solution remains
within a sterile fluid path at all times.
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Aseptic processing has been used for
decades to produce various sterile products. The technology has advanced
greatly from its origins when an operator would add solutions to a sterile vial
using a manual pipette in an unclassified
environment.
*O UIF 8PSME )FBMUI 0SHBOJ[Btion “standard” for aseptic filling includ-
ed the observation that microbiological
contamination rates for vaccines should
OPU FYDFFE (1). This is the earliest reference to media fill capabilities.
Technology certainly has enhanced our
expectations since that time. Robotic
filling equipment has replaced manual
filling, and cleanrooms have become
highly advanced to protect in-process
components from environmental contamination. Self-contained filling machines, such as blow-fill-seal technology,
have been developed and implemented.
Environmental control technologies,
e.g., isolators and restricted access barrier systems, have permitted advances
in the controls used in aseptic filling,
offering greater confidence in product
quality, particularly in the microbiological attribute of sterility. Common to all
of these technologies, however, is that
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environment, resulting in potential risks
for nonsterility.
Historically, these advances in aseptic
processing technologies occurred incrementally as subsets of the processes
involved achieved breakthrough discov-
eries. Many of these new technologies
took long periods of time to be accepted.
As noted by Russell Madsen, advanced
technologies used in aseptic processing
go through lifecycles that can be described as “S-curves” where the technology is discovered, matures, gains acceptance, undergoes refinements and then
may be replaced (2). Further, Madsen
pointed out that standards applied to
the old technology may remain in place
as a legacy notwithstanding that the new
technology does not benefit from the
old paradigm. As an example, he cited
“…the perceived need in unmanned
isolators for unidirectional airflow at
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widely adopted due to over caution.
For this reason, he expressed that the
industry and regulators should periodically reexamine well-established practices. We agree with his position that past
practices should be revisited when new
technologies make them unnecessary.
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In the case of closed filling technology, we assert there is no
benefit to the use of a classified environment for closed system
filling technology.
"DDPSEJOHUPBBSUJDMFJOPharmaceutical Engineering (3),
controlled nonclassified (CNC) manufacturing environments
are the next generation for pharmaceutical manufacturing, and
CNC is well suited to closed system filling.
To describe this new technology, we have presented its attributes in the form of an appendix, analogous to those in the
U.S. FDA Guidance for Industry: Sterile Drug Products Produced
by Aseptic Processing—Current Good Manufacturing Practice (4).
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World Health Organization Technical Report Series No. 530. World Health OrgaOJ[BUJPO
Madsen, R., “The Future of Aseptic Processing”, Pharmaceutical Technology TVQQMFNFOU Witcher, M.F., and Odum, J, “Biopharmaceutical Manufacturing in the Twenty-First Century – The Next Generation
Manufacturing Facility”, Pharmaceutical
Engineering FDA Guidance for Industry: Sterile
Drug Products Produced by Aseptic Processing — Current Good Manufacturing
Practice, U.S. Food and Drug AdminisUSBUJPO XXXGEBHPWEPXOMPBET
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A Rapid Method for Bioburden Testing of Disinfectant Samples continued from page 24
time to result with Staphylococcus aureus,
Aspergillus brasiliensis, Candida albicans,
Bacillus subtilis and Pseudomonas aeruginosa recovered on tryptic soy agar (TSA)
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Often the best way to overcome inhibition is through the development of an
appropriate rinse protocol. The three
SJOTFnVJETEFTDSJCFEJO641 Sterility Tests can also be used in bioburden
testing. The simplest rinse solution, fluid
A, is a neutral peptone solution. When
product sticks to the membrane, however, it may be necessary to use a surface
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28
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effective rinsing. Fluid D has the same
composition as fluid A, supplemented
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strongest rinse solution described is
fluid K, which contains beef extract and
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can inhibit recovery, so when fluid K is
used it should always be followed by a
final rinse with fluid A, PBS or sterile saMJOF 641 Microbial Examination
of Non-Sterile Products: Microbial Enumeration Tests also mentions the use of
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often used as diluents to improve filterability of samples.
Various combinations of prewetting solutions, diluents and rinses were tested.
Fluid D was shown to improve filterBCJMJUZUISPVHI˜NNJYFEDFMMVMPTF
ester (MCE) membrane and to eliminate
the inhibitory effects of the detergents.
In the final protocol, the membrane was
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of sample is adequate given that tightest
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was sufficient for the recovery all of the
organisms including Aspergillus brasilien-
Science
sis, the slowest grower, which can take up
to five days by traditional methods.
In the end, it was possible to test all
six detergents with the same method,
improving laboratory efficiency and re-
ducing the risk of operator error. Using Milliflex® Quantum for detection,
time to result was reduced from five
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Evaluation of Amplified-ATP Bioluminescence and Compendial Plate Count Methods continued from page 24
and sensitivity were determined using
a receiver operating characteristic table.
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parameters are presented in Table 1.
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The ATP+ method met or exceeded a
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parameters evaluated.
To further evaluate sensitivity, the limit
of detection (LOD) was calculated using
logistic regression where the response
variable is detection of a contaminant
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and 2 present the inverse interpolation
for the limit of detection on the log scale
for each test method.
Figure 2 Plate Count Method
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one-sided upper confidence limit on
the probability of detection. The solid
curved lines represent the predicted
probability of detecting an organism.
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dilution levels, at which the confidence
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The author believes that the data supports the notion that the method is equal to or better than the compendial method.
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