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Disposable Technologies for Aseptic Filling

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					Disposable Technologies
for Aseptic Filling
A Case Study
by Jan-Eric Zandbergen and Miriam Monge

                              Reprinted with permission from BioProcess International 4(6):S48-S51 (June 2006)




A
          global player in vaccine               MATERIALS TRANSFER                                 and maintenance. Typically a
          manufacturing, Solvay                  Having chosen isolator technology,                 traditional filling line requires two or
          Pharmaceuticals, has built             Solvay needed to determine how to                  three months of additional validation
          an influenza vaccine                   transfer materials in and out of an                just to start it up. That covers CIP
manufacturing facility based on cell             isolator without challenging their                 and SIP validation of the vessel and
culture technology to meet the                   cleanliness. Materials that need to be             transfer line, as well as the stopper–
growing worldwide demand for                     transferred include empty syringes,                plunger handling system. Additional
vaccines. Located in The Netherlands,            final bulk product in liquid form,                 maintenance costs (related to
this facility fills flu vaccine syringes         stoppers and plungers, environmental               replacement and labor) are associated
and will also act as a contractor for            monitoring samples, and filled                     with traditional facilities because of
filling and packaging similar                    syringes (Figure 1).                               the need to maintain vessels, washer,
products.                                           Traditional Material Transfer: In a             and transfer lines.
    This case study describes Solvay’s           traditional final-filling facility, stoppers           Alternative Technology Investigation:
project management activities for two            and plungers arrive loose and nonsterile           Needing to maintain a short project
newly installed high-speed, high-                in bags. They’re unloaded into a special           timeline while working in a
capacity, isolator-based filling lines in        washing machine that carries out                   multiproduct environment, Solvay
the Dutch final filling facility. Key            washing, siliconization, and                       decided to investigate alternative
project challenges the company faced             sterilization. Other materials are moved           technologies for materials transfer.
when installing these lines included             into the filling machine using rapid               The decision criteria for disposable
    • a short project timeline                   transfer ports. Formulated bulk fluid              technology were driven by the following:
    • the need for preventing                    arrives by a stainless steel vessel that has          • no cleaning (and thus no cleaning
contamination risk                               to be steam-connected to the line. Both            validation)
    • flexibility requirements                   transfer line and vessel must be cleaned              • no risk of cross-contamination in
(a multiproduct filling line)                    and sterilized in place (CIP, SIP).                a multiproduct environment
    • the need for high throughput                  Validation/Maintenance: All those                  • no steam sterilization validation
(with quick sanitization)                        materials require additional validation            for piping
    • necessary reliability (three shifts
for a June–September campaign)
    • validation and revalidation issues
relating to multiproduct operations
    • limited space (two filling lines,
maximum).
    Solvay chose to use isolators
because contamination risks are too
high in conventional cleanrooms for
seasonal products. No preservatives
are used in the flu vaccine
formulation. In addition, this vaccine
cannot be terminally sterilized.

                                                              Photo 1: Solvay Pharmaceuticals’ isolator filling line in The Netherlands
48 BioProcess International         J UNE 2006                                                                                            SUPPLEMENT
                                              Figure 1: Materials transfer into and out of an isolator filling line
   • no autoclave-loading validation
                                                                                                        ��������������������
   • use of presterilized, preassembled
                                                                                                          �����������������
components (no manipulations after                   ������������������������
sterilization).                                     ������������������������
   Isolators allowed use of several
single-use technologies:
decontamination chambers for empty
syringes; a disposable bag system for
                                                                                             ��������������
bulk fluids; rapid exchange ports from
Isolateur Dénominateur Commun
(IDC, www.idcbio.com) for transfer                                                                                                  �����������������
of fluid, stoppers and plungers, and                                                                                                 ������������
environmental monitoring samples into                                                                                                 �������������
                                                                                                                                         �����
and out of the isolators; and “mouse                     ���������������������                        ��������������������
holes” for transfer of filled syringes.                       ������������                            ���������������������
                                                             ����������������                          ��������������
THE DISPOSABLE TECHNOLOGY                                                                                  �����������        ������������
For this filling line, isolators are housed                                                                                     �������
in a Class D environment. Photo 1
shows the Solvay filling line based on
disposable technologies used to fill          Figure 2: Solvay Pharmaceuticals’ filling line
syringes with flu vaccine. The facility                                                  ��������             ��������
incorporates two filling lines rated to
fill 18,000 syringes per hour. Empties
arrive at the filling line in sealed tubs,
each of which contains 200 syringes. A
                                                                  ����                                   ��                         ������
total of nine tubs (1800 syringes) are
                                                             ���                                    �����                           ��������
loaded into a decontamination unit,
which cleans only the outside of the
container because the syringes inside
are clean and sterile.                                                 �  ����             ����               ���������
    As Shown in Figure 2: When the                            ��   ���                   ���������             �������
tubs enter the “peeling” section, a top               ��  ���
plastic layer is peeled off to reveal
sterile syringes. Those move into the                       �������
                                                                 �                                 ������������������������
filling section, where they are filled                       ����
(for the flu vaccine, a 0.5-mL fill). A
stopper is then applied to each syringe          • Kleenpak brand connectors from
to seal the product formulation inside,       Pall Corporation (www.pall.com) for
and then a separate plunger is added.         rapid aseptic fluid flow connections.
Filled, sealed syringes then leave the           The disposable bags, transfer sets,
isolator in their tubs.                       connectors, and rapid-transfer ports
    Gamma-irradiated plungers and             were delivered preassembled and
stoppers arrive in their own disposable       gamma sterilized, ready for aseptic
bags, which come with an IDC beta             fluid transfer. Because of this
Biosafe docking port. A bag is docked         preassembled, totally closed, gamma-
to the isolator and unloaded internally       sterilized single-use system, no class-A
into feed hoppers. All in all, it takes       laminar air flow is necessary. Six IDC
1.5–2.0 hours to prepare the line.            rapid-transfer ports allow all necessary
    Highlighted disposable technologies       entry of the isolator filling line.
for the filling line include the following:      Fluid Transfer: Fluid is aseptically
    • IDC Biosafe rapid-transfer ports        transferred from the disposable Flexel
for both solids and aseptic fluids transfer   3D bag into the isolator by a Stedim
onto the line, allowing disposable bags       rapid aseptic transfer system (RAFT),
to be docked to the isolators                 using in this case an in-line
                                                                                                      Photo 2: A Flexel 3D bag and Palletank vessel
    • 500-L disposable Flexel 3D brand        combination of the Pall Kleenpak
                                                                                                       are shown with a transfer set and IDC alpha
bags from Stedim (www.stedim.com)             aseptic connector, a transfer set, and                   and beta Biosafe ports docked to the Solvay
for storing the bulk flu vaccine              the IDC Biosafe rapid exchange port.                          Pharmaceuticals isolator filling line.

SUPPLEMENT                                                                                       J UNE 2006           BioProcess International      49
 Figure 3: The IDC Biosafe port and rapid aseptic transfer port in operation
                                                                                                             • consumable costs (disposable
                                                                                                          bags, connectors, stoppers, plungers,
                ������������
               ��������������                                                   �����������������         and spares)
                                                                                �����������������            • material costs (chemicals, WFI,
                                                                                ��������������
                                                                                                          purified water, and steam incurred in
                                                                                                          running the process, cleaning, and
  ������                                                                                                  sterilization)
   ����                                                                                                      • labor costs (direct production,
                                �������                                                                   quality, and maintenance).
                                 �����                                                                       The COG model estimates the cost
                                                                                                          differences between disposable and
                                                    ������
                                                                                �������                   traditional filling technologies, which
                           �����������              ����
                           ����                     ���                         ���������                 allowed Solvay to compare the two
                                                                                                          methods for cost effectiveness. Costs
                                                                                                          are expressed per batch for each
                                                             ���������������������������������������      option. In addition, savings for each
      ����                                                                                                category were calculated to identify
     ������
                �������                                                                                   where cost differences occurred. A
                ���������                                                                                 case study was presented for evaluating
                                                                                                          the relative economic feasibility of a
    Figure 3 illustrates the fluid                      traditional filling line the stoppers and         disposable filling facility and a
transfer process. A gamma-sterilized                    plungers arrive loose and nonsterile in           traditional reusable facility. In Table 1,
bag arrives with its aseptic connector                  bags. They are unloaded into a special            negative values occur where the
and transfer set attached. After QC                     washing machine that washes,                      disposable option is more expensive
samples are taken, fluid is pumped to                   siliconizes, and sterilizes them.                 than the traditional facility.
the sterilizing filter, with a 5-L                                                                           These model results show that
Flexboy bag acting as a vent (Solvay                    COST COMPARISON                                   disposable filling technology is more
requires a closed-bag system for                        Part of Solvay’s project analysis was to          economically viable than traditional
venting to prevent sterility                            evaluate the relative economic                    reusable technology. The single-use
compromises). Further along the line,                   attractiveness of the disposable and              option benefits from reduced capital
a Flexboy bag collects the first half-                  traditional filling technologies. A               charges (48%) because of lesser
liter of bulk liquid that rinses the                    cost-of-goods (COG) model was                     equipment requirements. Its disposable
filter. A specially designed 10-L                       developed for both the disposable and             nature eliminates the need for
intermediate bag acts as a reservoir for                traditional reusable filling facilities           cleaning and sterilization. So the
regulating the amount of buffer that                    by expert consultants in economical               disposable filling facility benefits from
feeds onto the syringe filling line. It                 modeling (Biopharm Services,                      lower operating costs incurred for the
is connected to the isolator through                    www.biopharmservices.com). Based                  material and labor cost categories (cost
an IDC alpha/beta Biosafe door and                      on a Microsoft Excel spreadsheet, the             reduction estimated at 5% and 25%
Kleenpak connector.                                     model breaks down the following cost              respectively). However, there is a 37%
  Transfer of Stoppers, Plungers, and                   categories (Figure 4):                            increase in the costs of consumables
Samples: As mentioned, in a                                • capital charges                              because of the presterilized and ready-




                                                                                    Photo 4: Environmental monitoring (EM) samples can be transferred
   Photo 3: In the Solvay facility, plungers and stoppers arrive gamma-                 from the isolator through an IDC beta Biosafe port system.
irradiated and contained in a disposable bag that has an IDC beta Biosafe
   port to dock with the alpha Biosafe on the isolator for aseptic transfer.
50   BioProcess International              J UNE 2006                                                                                         SUPPLEMENT
                                           Table 1: Cost breakdown
to-use stoppers and plungers sold
                                                                                                                             Cost Savings
in disposable bags. Although the
                                            Cost Category                  Disposables           Traditional            Per Batch    Percentage
disposable option has higher
                                            Capital                              40                 54,196                54,156         48%
consumable costs, its overall running
                                            Consumables                      58,368                  17,013              –41,355        –37%
costs are 41% lower than those of
                                            Materials                             0                   5,310                5,310          5%
traditional reusable technology.
                                            Labor                             8,266                 36,387                28,121         25%
    Solvay carried out a sensitivity
                                            Total                            66,673                112,905                46,232         41%
analysis to investigate the effects of
various scenarios on COG savings for
the disposable filling option. This        Table 2: COG results of the sensitivity analysis        Figure 4: Cost breakdown
enabled decision-makers to examine                                         Scenario                             �     �����       �����������
the variability of key input parameters                                                                      ��
                                            Cost Category              A              B                   �� ���      ���������   ���������������
                                                                                                       �� �
on those cost outputs.                      Capital charges          63%          60%                �� ����
    Sensitivity analysis provides an        Consumables              –26%         –27%              ���
organized and systematic way to             Materials                 3%           4%
                                                                                                    ���
investigate the impact of key input         Labor                    20%           21%
parameters on the stability of a base       Total                    60%          58%                 ��
case. Biopharm Services carried out                                                                   ��
a sensitivity analysis for Solvay to          In a facility working with
investigate the effects on COG for         traditional technologies, COG rises                        ��
both a disposable and a traditional        dramatically as plant use drops — so                       ��
filling facility. A sensitivity analysis   the COG benefits of disposables are
                                                                                                       �
was then carried out for each variable     even greater with lower overall use.                            ����������         �����������
in those scenarios, keeping all other      Using disposables allows you to divert
variables fixed at the baseline value      fixed capital costs into variable
each time. In Scenario A, batch size       consumables costs, which helps                         SOME FILL-AND-FINISH
was reduced to 200 L. In Scenario B,       manage uncertainty such as whether                     TERMINOLOGY USED HERE
syringe fill volumes were increased to     the filling lines run at full capacity for             alpha port: transfer port mounted on a
1 mL. Table 2 summarizes the cost          contract manufacturing outside the                     cleanroom or isolator wall
savings. Cost values are for the           seasonal flu vaccine filling activity.                 beta port: mobile container port that
single-use system relative to the          This is important when evaluating the                  connects to an alpha port for transfer
traditional reusable option.               use of disposable technologies, if you
                                                                                                  mouse hole: open space (generally
    In scenario A, with the batch size     consider that capacity use for all                     small) between two different zones;
reduced to 200 L, an overall savings       biomanufacturers with mammalian                        protected from contamination with a
of 60% is estimated for the disposable     cell culture systems is currently 68.8%                dedicated air flow system
filling option. Reduction of batch size    (2). In a future article, we plan to                   peeling: peeling off of a Tyvek face
has increased the cost savings 19%         address this in more detail.                           welded onto a tub (container)
from the base case. The model results
                                                                                                  siliconize: coating stoppers and
indicate that for scenario B, in which     INTERIM RESULTS                                        plungers with silicone to facilitate their
the syringe fill volume is increased to    To date, 250,000 syringes have been                    entry into syringes
1 mL, a 58% cost savings is realized       successfully filled in this facility, and
for the disposable filling facility.       they were all successful. More than
    Benefits: This kind of COG model       100 Kleenpak and more than 4000                       REFERENCE
offers several useful functions. Users     Biosafe connections have been made.                       1 Langer E, Ranck J. Capacity Bottleneck

                                                                                                 BioProcess International 4(3) 2006: 14–18. 
                                                                                                 Squeezed By Downstream Processing.
can define key input parameters and        The technology continues to be fine-
view resultant cost outputs. The model     tuned, with development of a
provides a breakdown of COG in             disposable filling station in progress.
different cost categories. Decision-       An additional benefit of working with                 Jan-Eric Zandbergen is sterile production
makers can evaluate process economics      disposable systems is that design                     manager at Solvay Pharmaceuticals in Olst,
for the two filling technologies and       optimization can be carried out very                  The Netherlands, jan-eric.zandbergen@
perform sensitivity analyses of key        simply without having to take out                     solvay.com. Corresponding author Miriam
input variables to determine their         existing equipment.                                   Monge is marketing director at Stedim
impact on cost.                                By working with disposables                       headquarters, Z.I. des Paluds, Ave de Jouques
                                                                                                 – BP 1051, 13781 Aubagne cedex, France,
    Certain additional factors were not    technology, Solvay has developed two
                                                                                                 33-442-84-56-11, m-monge@stedim.fr.
calculated in that analysis: Faster        highly efficient and safe multiproduct
turn-around times translate to higher      filling lines. The sterile production
throughput when working with               manager says, “I would definitely
disposables.                               choose the same approach again.”

SUPPLEMENT                                                                                    J UNE 2006            BioProcess International    51