Aseptic Formulation

and Filling Using

T
he number of parenteral products entering development
and reaching the market has increased significantly dur-
ing the past decade. By some estimates as many as half
of all investigational new drug applications consist of
biopharmaceuticals, the vast majority of which are manufac-
Isolator technology can be tured aseptically. Most of these products are proteins and there-
fore highly susceptible to microbial contamination. In addition,
used in clinical product
regulatory agencies around the world are devising and enforc-
formulation and filling ing increasingly stringent requirements for environmental and
facilities to ensure process control in aseptic processing. These factors are creat-
environmental control and ing interest in advanced aseptic technologies that provide su-
reduce contamination risk perior contamination control.
during aseptic processing. Key Historically, the construction of an aseptic processing suite
for small-scale or clinical-size batches has been a time consum-
features of the filling system
ing and expensive venture. Depending upon a facility’s starting
include mass flow technology point, construction can take 18–36 months. If an existing room
and a filtration skid that can or suite of rooms is to be remodeled, it may be possible to have
be cleaned and sterilized in a fully validated and functional facility in 18–24 months, de-
place. The process can pending upon the scope and complexity of the manufacturing
accommodate vials and requirements. However, if a facility must be built in a “green
field,” or if a new construction is attached to an existing struc-
ampuls and can provide
ture, the time to completion may be much longer, frequently on
lyophilization capability. the order of 30–36 months. Validation of even a small-scale asep-
tic processing facility can take 3–6 months or more, depending
on the size of the facility and the type of equipment required. It
is not uncommon for a project that consists of building and val-
idating a clinical or small-scale aseptic processing facility to cost
more than $10 million, which does not include ancillary costs
Frank DeSantis, PhD, is executive
director, pharmaceutics, Kent Amsberry
such as staffing and training a highly specialized cadre of oper-
PhD, is group leader, pharmaceutics, and ational, quality assurance, and compliance personnel.
Jeff L. Folks is director of business After completion, such facilities can be costly to operate be-
development at Quintiles (Kansas City, MO), cause of several factors, not the least of which are high energy
tel. 816.767.3836, fax 816.767.3950, costs as a result of extensive air-handling requirements. Even
jeff.folks@quintiles.com. Atsushi Yamamori
is general manager of the international
though small-scale facilities are generally not in continuous use,
marketing division of Shibuya Kogyo Co. Ltd. most firms find that running air-handling systems continuously
(Kanazawa, Japan), and James Akers, is necessary to maintain the exacting level of contamination con-
PhD, is president of Akers, Kennedy and trol required by the regulations. In addition, monitoring the en-
Associates (Kansas City, MO). vironment generally is required at all times, which requires ex-
*To whom all correspondence should be addressed. pensive gowning supplies and consumables even when the facility
is not in production.
32 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com
Isolator Technology
A technology that has gained acceptance during the past the daily costs to maintain the facility are greatly reduced. Main-
decade is isolator technology, although this technological solu- taining the aseptic atmosphere during the manufacture of clin-
tion has not frequently been applied to small-scale or clinical ical supplies is more efficient with the use of isolator technol-
manufacturing. Isolator technology can reduce project time- ogy because the chief source of contamination, the human
lines, increase environmental quality, and reduce operating costs. operator, is more effectively separated from the production
Of course, for these benefits to be realized, some important con- environment than is possible in a conventional human-scale
ditions must exist. First, the firm undertaking the project must cleanroom. In addition, the isolator can be decontaminated
be willing to move into new technology. Second, the project with a sporicide such as vapor hydrogen peroxide (VHP) to en-
team must establish clear objectives and logical, well-defined sure that the bioburden within isolator enclosures is maintained
user-requirement specifications based on current regulatory at levels that would be unattainable in a conventional clean-
expectations and technological feasibility. Third, equipment room. Components and other manufacturing supplies are trans-
vendors must be selected that can provide isolator-compatible ferred into isolators using reliable transfer ports and are main-
equipment in a timely manner. tained in clean environments within the isolator units.
Facility design and construction costs generally are consid- The following is a description of a new isolator-based asep-
erably lower in aseptic processing facilities that are designed tic facility being installed at Quintiles, Inc.’s Kansas City, Mis-
around isolator technology. Aseptic processing in conventional souri site. This facility was designed to comply with PDA T/R34,
staffed cleanrooms requires large, human-scale rooms with the guidance on isolators provided by FDA’s 2002 concept paper
cleanliness zones, each of which must be operated and con- on aseptic processing. Other international guidance and stan-
trolled to a specific pressure differential. These facilities also re- dards such as that produced by PIC/S, ISO, and USP were con-
quire three-stage gowning facilities for staff entry as well as exit sidered. The result is a facility designed to operate in compli-
rooms for removing gowns. Air locks with air-handling systems ance with all current and anticipated international requirements
are required for materials entry and the removal of waste and for aseptic processing.
quality-control samples. Human-scale facilities generally con-
sist of ISO Class 6 or 7 filling rooms in which a Class 5 aseptic The process
critical zone is located and used for all aseptic filling, stopper- Filling. The isolator and the filling system enclosed within it were
ing, and sealing operations. (ISO 14644 1–3 has replaced US manufactured by Shibuya Kogyo Co. Ltd. (Kanazawa, Japan).
Federal Standard 209E. ISO Classes 5, 6, 7, and 8 are equivalent The isolator has a rigid-wall construction (model PRLF20710)
to Federal Standard 209E Classes 100, 1000, 10,000, and 100,000, and is equipped with HEPA-filtered, recirculated, unidirectional
respectively) (1). Fill rooms are supported by component entry airflow to provide an ISO Class 5 (EU Class A) environment
rooms, employee entry corridors, and other support areas as under dynamic conditions and an ISO Class 4 environment
required (e.g., lyophilizer rooms). These facilities are expensive under static conditions.
to design, build, and maintain. The isolator will be decontaminated using vapor hydrogen
Isolator-based aseptic processing facilities are less complex peroxide (VHP) generated by a Steris VHP–1000ED–C. The ef-
and easier to design and build. Generally, all isolators are lo- fectiveness of the decontamination process will be validated to
cated in an ISO Class 8 environment (2). This obviates the need produce complete kill of biological indicators (BIs) containing
for three-stage gowning because full aseptic suits are not needed. a population of
106 Geobacillus stearothermophilus spores,
All aseptic activities are conducted in the locally controlled ISO providing a total spore log-reduction value of at least 8 logs (3).
Class 5 environments provided by stationary and mobile (trans- The BI substrate is stainless steel, and a sufficient number of
fer) isolators. Therefore, the background environments can all BIs will be placed throughout the filling isolator to ensure the
be considered equivalent from an air-quality perspective, and complete elimination of bioburden with a high margin of safety.
pressure-differential cascades are not required. These facilities The isolator and filling system were designed to exacting
also can make greater use of available space because internal hygienic standards to ensure the absence of biofilm and a con-
partitioning requirements are reduced. sistently low bioburden before decontamination. In the event
Depending on the starting point, a small-scale aseptic pro- that potent drugs are manufactured within the filling isolator,
cessing facility based on isolator technology can be up and run- the isolator is equipped with easily changed HEPA filters to
ning in 12–18 months at a cost of $3–5 million. This of course facilitate the replacement of the filters.
requires that facility design and construction be done in par- The filling system (model Perflac 9001S) is a single-head sys-
allel with equipment selection and construction. Careful tem capable of filling 600–1500 units/h depending on the type
coordination among vendors is required, and a great deal of and volume of the container. The filling system will process vials
attention must be paid to ergonomics and equipment interac- and ampuls and will contain stations to stopper (fully or par-
tion. However, the benefits are lower cost, a shorter path to tially) and cap (aluminum with plastic flip-off) vials and heat-
return-on-investment, and a higher-quality manufacturing seal ampuls. For oxygen-sensitive products, an inert-gas purge
environment that is more likely to meet increasingly stringent system can be used with both vials and ampuls. Purging can be
aseptic processing regulations. done both before and after filling so that a low level of residual
For small batch sizes and early development of sterile prod- oxygen can be ensured immediately before stopper placement
ucts, the use of isolator technology offers benefits over the use in vials or heat-sealing of ampuls.
of a sterile room. With only the isolators at an ISO Class 5 level, All parts within the filling system’s fluid delivery pathway are
34 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com
Isolator Technology
transferred into the filling isolator using a larger (350–alpha)
Initial setting for fill Setting for fill volume per RTP that is attached just above an accumulation platform lo-
volume per 1 pulse 1 pulse for calculation of
display mass flow
cated inside the isolator. Trays of vials or ampuls will have been
(X g/pulse setting)
previously placed in a transfer isolator (TI) (la Calhène) through
an oven-interface isolator (la Calhène) after being washed and
Transmitter PLC Touch panel
depyrogenated in a Despatch (Lakeville, MN) batch oven
equipped with Class 5 quality HEPA-filtered air. The TI is fit-
Pulse signal Mass flow
display
ted with a 350–beta flange through which it will be docked to
Flow Pressurization the corresponding 350–alpha RTP on the filling isolator. With
regulating the use of glove ports on the TI and filling isolator, trays of glass-
value Manifold
ware will be transferred onto the accumulation platform. Then
Mass flowmeter with the use of glove ports attached to the isolator, the vials or
Magnet
ampuls will be removed from the trays and loaded onto a con-
valve
veyer that will feed the vials or ampuls into the supply screw
feeder of the filler.
The filling system can accurately fill volumes from 0.5 mL to
25 mL with a standard deviation of less than ± 0.02 g in filling
1 g and  1% in filling 1 g (n = 30, using water). The fill-
Figure 1: Mass flow rate filling–system structure. volume range is accomplished with the use of four nozzles of
various sizes. Fill volume is measured by a mass flowmeter
cleaned and sterilized in place. This provides quick and efficient (Micro Motion, St. Louis, MO), which is described later in this
changeover from one lot to the next and may obviate the need article. The fill volume of each unit can be recorded and stored
for VHP decontamination between the filling of different prod- electronically. Liquid-filled vials that are outside the set fill range
ucts that use the same component configuration. Changeover will be automatically rejected onto a reject conveyor and re-
from one component configuration to the other can be accom- moved from the isolator at the end of the run. Another mech-
plished in 1 h. In such cases VHP decontamination and aer- anism will automatically reject improperly capped vials. If an
ation of the filling system and isolator are required. ampul fill is outside of its fill range, then the machine will stop
Compounded liquid product is sterilized by a filter skid that feeding ampuls and the out-of-specification ampul will be man-
is capable of accommodating various types of standard filter ually removed as it exits the isolator. An operator will then restart
cartridges and therefore is adaptable to the needs of almost all the filling process. Both the isolator and filling machine are
liquid products. The filter skid is sterilized in place along with completely controlled (including the setting of filling parame-
the fluid path of the filling system. The filter skid has an inte- ters) by an external control panel, thereby minimizing the need
grated Millipore Integritest system, which allows the sterilizing for manual intervention during the filling process.
grade filter to be integrity tested in situ after steam sterilization. The filling process involves applying filtered compressed air
For additional assurance of system integrity, the filter can be or nitrogen at a specified pressure to the upstream side of the fil-
retested after filling. The filling system is connected with PTFE tration skid. This forces the compounded product through the
tube piping to the flow-metering unit, which houses a small sterilizing-grade filter into the small manifold located in the
manifold and mass flowmeter (MFM) that regulates the liquid flowmetering unit, which is located upstream of the MFM (see
volume delivery. The entire system, including the filtration skid, Figure 1). The programmable logic controller (PLC) of the fill-
flowmetering unit, and filling nozzle, can be dried with filtered ing machine uses an electronically controlled valve to regulate
compressed air or nitrogen to minimize product loss as a result the volume of filtered sterilized product in the manifold. The
of initial dilution with residual water for injection (WFI). MFM measures and controls fill volume using an electronic trans-
For loading clean, sterilized stoppers and aluminum flip-off mitter that interfaces with the filling system PLC.
caps onto hoppers within the isolator, the wall of the isolator is The MFM measures fill weight using the Coriolis principle.
fitted with two 190–alpha rapid transfer ports (RTPs), manu- The unit measures mass flow and density of the liquid being
factured by la Calhène (Rush City, MN), directly above each filled to convert mass flow (g/s) to fill volume (mL/unit). The
hopper. The stoppers and flip-off caps will have been previously mass flow unit is depicted in Figure 2. Liquid entering the sen-
sterilized in an autoclave by placing them in nonwoven high- sor is split into two flow tubes, each of which has the same total
density polyethylene bags attached to a 190–beta flange (la Cal- volumetric capacity. The flow tubes oscillate up and down in
hène). The aseptic transfer is accomplished by mating the alpha opposite directions, and this movement is detected and trans-
and beta halves of the RTP and opening the RTP from inside mitted to the PLC using “pickoffs” consisting of a magnet and
the isolator using an attached glove port. The stoppers or flip- coil assembly mounted on the flow tubes on both the inlet and
off seals are then pushed into the hopper using the nonwoven outlet sides. The oscillation of both the inlet and outlet side is
high-density polyethylene material of the bag to maintain a recorded as a sine wave by a sensor–transmitter. When there is
sterile component-feed pathway and to reduce the need for in- no movement, the sine waves from the inlet and outlet pick-
tervention with gloved hands. off are superimposed or in phase. When there is movement of
Previously washed and depyrogenated ampuls or vials are fluid, Coriolis forces are induced. These forces cause the flow
36 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com
Isolator Technology
tubes to twist in opposition to each other. As a result of the
twist of the flow tubes, the sine waves generated by the pick-
offs are now out of phase because the inlet side is lagging be- Flow inlet
hind the outlet side. The magnitude of the out-of-phase force
is measured as the time difference (∆t), in microseconds, be- Drive coil
tween the height of the inlet sine wave and that of the outlet and magnet
sine wave. The magnitude of ∆t is proportional to mass flow
(g/s). Mass flow is calculated by multiplying ∆t by the instru- Flow tubes
ment’s specific flow calibration factor, which is determined
during factory calibration of the mass flow unit. The density Flow outlet
of the liquid is inversely proportional to the period of the sine
waves. Each transmitter–sensor pair is factory calibrated be-
fore shipment for flow and density calibration. Flow and den-
sity calibration factors are stored in the transmitter’s memory Figure 2: Mass flow device.
to automatically perform the necessary calculations to deter-
mine mass flow and volume fill.
Capped vials (liquid or freeze-dried) and sealed ampuls will tween the vials and the shelves. The lyophilizer will have five
be discharged from the filling isolator through separate open- usable shelves located in a single chamber with a total surface
ings. Air pressure at each opening is positive to the ISO Class 8 area of 1.3 m2. With full loading, the unit will be able to process
room to maintain the aseptic environment of the isolator and
1400–5200 vials per batch, depending upon vial size. The unit
validated to demonstrate environmental integrity. The open- will have one horizontal ice condenser separated from the cham-
ings will be kept closed when not in use. Partially stoppered ber by a pneumatically operated butterfly valve. The chamber
vials for lyophilization will exit the isolator through a different will be evacuated by an oil-sealed, two-stage vacuum pump.
350–alpha RTP. Another TI, fitted with a corresponding 350–beta The vacuum level of the chamber will be monitored and con-
RTP, will be docked to the exit. Using the glove ports of the iso- trolled using an MKS capacitance manometer. The chamber is
lator and TI, the partially stoppered vials will be loaded onto cleaned in place (CIP) by filling the chamber with WFI and is
freeze-drying trays in the isolator and then passed through to steamed in place (SIP) by flooding the chamber with clean
the TI for transport to the freeze dryer. The vials containing steam. A liquid ring pump is used to dry the chamber follow-
freeze-dried product are fully stoppered in the lyophilizer and ing a CIP or SIP cycle. Two independent single-purpose refrig-
then transported back into the filling isolator for capping as eration circuits or compressors are provided for shelf and con-
described previously for transferring empty vials into the fill- denser coil cooling. The shelves can be cooled to 55 C and
ing isolator. Particles generated in the ampul sealing and vial- heated to 70 C. Shelf heating and cooling is achieved using
capping sections of the isolator are prevented from entering the an immersible electrical heater and the shelf refrigeration cir-
filling section by differential pressure and airflow management cuit. The chamber normally operates under a high vacuum
(the pressure in the filling section is greater). achieved using the two-stage vacuum pump. During the subli-
Lyophilization. Lyophilization, or freeze-drying, is an important mation process, large quantities of vapor are released from the
pharmaceutical process because it enables the removal of water, product and these are condensed on the chilled condenser coils.
through the sublimation of ice, at low temperatures. Lyophiliza- Condensing the vapor on the condenser coils prevents conta-
tion has several advantages over other methods of product dry- mination of the vacuum pump. The condenser coils are chilled
ing. Because lyophilization occurs at low temperatures, chemical to an ultimate minimum temperature of 70 C. Filtered ni-
decomposition of heat-sensitive products such as biologicals is trogen is bled into the chamber during processing to control
minimized. The resulting product has a very large specific surface the vacuum level in the chamber. Nitrogen also is used to re-
area, which promotes rapid and complete dissolution upon re- lease the vacuum in the chamber at the end of the lyophiliza-
constitution. Lyophilization is highly compatible with aseptic op- tion process. A hydraulic pump is used to operate the shelf-
erations because the product solution can be sterilized by filtra- positioning hydraulic ram to seat the stoppers at the end of the
tion before lyophilization. This type of process allows for more process. The lyophilization cycle is controlled using a Lyomas-
precise liquid filling and less particulate contamination in the ter personal computer using Windows XP and Intellution iFIX
aseptic environment than a comparable powder filling operation. software with a lower level of control provided by a PLC.
In this facility, filled and partially stoppered vials will be
lyophilized using a BOC Edwards Lyoflex 1.3 lyophilizer. The Validation and process control
lyophilizer will have a monoblock design with all components Isolators. The clinical filling system described in this article op-
mounted to a single frame. The lyophilizer chamber door ex- erates using an “islands of isolation” strategy consisting of a net-
tends through the wall into the sterilized interface isolator while work of stationary isolators, each of which serves a single piece
the remainder of the unit is located in a nonsterile utility room. of equipment. Two TIs serve as shuttles to move sterilized com-
The product is loaded onto the shelves from the interface iso- ponents to the filling isolator, partially stoppered vials to the
lator by an operator in a half suit. The product is loaded in trays lyophilizer, and fully stoppered lyophilized vials back to the fill
with removable bottoms to facilitate good thermal contact be- isolator for sealing.
38 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com
Isolator Technology
There are two interface isolators, one attached to a Despatch standard operating procedures (SOPs) will be developed to
batch depyrogenation/sterilization oven and the other attached define in-process integrity test conditions. A full environmen-
to the Edwards lyophilizer. Both interface isolators are flexible- tal monitoring performance qualification will be done to demon-
wall, engineered, turbulent-flow, closed isolator units equipped strate the ability of the isolator to maintain aseptic conditions
with half suits. Each of the interface isolators will be deconta- for the unit’s defined operational period. As is the case for all
minated using a Steris VHP–1000ED–C vapor hydrogen per- isolators in the network, we expect that the filling isolator will
oxide generator. The cycles will be developed by evaluating tem- remain free of detectable bioburden.
perature conditions in the isolator during decontamination and Preparation of containers and closures.The filling system can ac-
an injection rate will be chosen to provide the optimal con- commodate various vials and ampuls. Each vial and ampul sys-
centration of vapor hydrogen peroxide relative to the dew point. tem will be washed using a Cozzoli glassware washer. The effi-
The decontamination cycles will be demonstrated to achieve a cacy of the washer will be verified by particulate removal studies
complete kill of a sufficient number of BIs of G. stearother- on glass containers. After washing, the trayed glassware will be
mophilus with a population of
106 spores/indicator. Three full sterilized and depyrogenated in a Despatch batch oven equipped
tests with BIs will be conducted to verify decontamination cycle with high-temperature HEPA filters so that ISO Class 5 condi-
efficacy. tions can be maintained during operation. The ability of the
The TIs are flexible-wall turbulent-flow closed isolators oven to maintain this particulate air quality and to achieve tar-
equipped with three glove–sleeve assemblies. The flexible wall geted temperature will be verified. The depyrogenation process
design was selected because of its reliability and because its rel- will be validated to provide a minimum 3–log reduction of ref-
atively light weight enhances maneuverability. Transfer bridges erence standard endotoxin inoculated onto test glass (5).
custom built and ergonomically tested will facilitate movement Rubber closures for vials will be purchased prewashed from
of container trays into and out of the TIs. An identical decon- vendors and sterilized in nonwoven high-density polyethylene
tamination strategy will be used for the isolators. Because these beta-bags as previously described. The mass of stoppers placed
isolators will be used only to transfer sterilized materials, the in each bag will be verified to ensure load uniformity. The stop-
TIs will be decontaminated without removing shelves or ma- pers will be sterilized in a Fedgari autoclave which will be val-
terials handling tools. A sufficient number of BIs will be placed idated in the conventional manner. Temperature penetration
throughout the isolators to verify the effectiveness of the de- and distribution studies will be conducted and the delivery of
contamination process. lethality sufficient to achieve a 106 probability of nonsterility
The TIs and interface isolators also will provide an environ- will be verified by BI challenges.
ment that is consistently free of microbiological contamination Cleaning and sterilization of the fluid path. The sterilization of
throughout the designated use period. This will be validated by the Shibuya product filter skid and mass-flow filling system will
a comprehensive microbiological monitoring program using be validated to demonstrate a 106 probability of nonsterility.
both surface and active air-sampling methods. It is expected Temperature distribution throughout the fluid path will be as-
that all microbial samples will be free of contamination. The sessed, and BIs will be used to confirm lethality. From the steril-
isolator air-handling system will be verified to comply with ISO ity assurance perspective it is advantageous that the fluid path
Class 5 conditions and the ability of the isolators to control to is sterilized fully assembled and ready to operate and no asep-
the required overpressure set point also will be verified. tic connections are required.
After the completion of validation, routine environmental The entire fluid path will be cleaned in place and tempera-
monitoring for both viable and total particulate will ensure that tures and flow rates will be verified against the system’s user
the isolators continue to provide a suitable environment for requirement specifications. Cleaning acceptance criteria will be
aseptic processing. The target contamination levels for the flex- developed for each clinical material filled on the system con-
ible wall isolators will be zero. Should viable counts be found, sidering the toxicological characteristics of the product. The
a thorough investigation will be conducted and appropriate ac- acceptable carryover value will be determined using a starting
tion taken to ensure that the environment is free of microbial point of either 1/1000 of the minimum therapeutic dose or a
contamination (4). no-observable-effect-level model. The safest approach to
The filling isolator is a rigid-wall, unidirectional airflow, open determining carryover will always be chosen (6).
isolator. This isolator has openings to allow for the removal of Filling accuracy. The ability of the filling system to deliver
sealed vials or ampuls. The isolator will be validated to demon- accurate volumes will be verified over the specified volume
strate that ISO Class 5 air-quality conditions can be maintained delivery range. The filling control loop will be verified as well.
during operation and to demonstrate that the openings are After validation, the system will be checked for accuracy dur-
effectively sealed by air overpressure. ing setup and will be calibrated on a regularly scheduled basis.
The filling isolator will be decontaminated using the same Because the Shibuya filler provides weight control data on each
methods and to the same specification as previously described container, there will be no need for manual in-process weight
for the interface and transfer isolators. To ensure safety, the iso- checking.
lator will be decontaminated with the exit doors closed. Stopper and seal feeding system. The parts hoppers for both the
The ability of the isolator air-handling control PLC to con- rubber stopper and aluminum seals are located inside the Class
trol air pressure in the isolator to set point will be verified. The 5 decontaminated isolator environment and will be decontam-
integrity of the isolator will be demonstrated in validation, and inated in situ using VHP. The parts hoppers and feed tracks will
40 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com
Isolator Technology
be cleaned after each use to remove process-related dust and fill tests, and the containers will be incubated for 7 days at 20–
lubricants. This system has two substantial advantages over typ- 25 C followed by 7 days at 30–35 C. It is expected that all media
ical cleanroom installations. First, there is no aseptic assembly fills will be completely free of microbial growth (8).
required, and second, the capping machine is within a section
of the isolator. The design provides separation so that particu- Regulatory compliance
late generated during sealing can not affect product, but it also Care has been taken in the design of the aseptic processing
ensures that sealing is performed in the same high-quality en- facility to ensure that it will comply with all global regulatory
vironment as filling and stoppering. This ensures complete pro- requirements. Current regulatory guidelines require clinical
tection of the entire container assembly process from microbial product to have the same sterility assurance as commercial prod-
contamination for optimum assurance of safety. uct. Therefore, the facility was designed to provide contamina-
The stopper-placement system will be validated to reliably tion control superior to that of any staffed cleanroom and to
fill and half-stopper vials. The system will be shown to meet a achieve near-zero contamination results in environmental mon-
consistent process capability requirement. The capper will be itoring and media-fill testing. The validation and process con-
validated to demonstrate the application of consistent seal-force trol programs are of the same standard as would be applied to
pressure. The total container closure integrity of each container a commercial aseptic processing facility.
will be verified by microbial immersion testing. The filler is
capable of inert-gas overlay, and this system will be validated Summary and conclusions
to demonstrate that it can achieve suitable levels of residual oxy- The scientists and engineers involved in this project have
gen on a product-by-product basis. endeavored to design and equip a facility that will manufacture
Lyophilizer sterilization. The Edwards lyophilizer is designed safe and contamination-free clinical products. The timeline is
to be sterilized in place by moist heat. Temperature distribu- ambitious and the company plans to have the facility fully func-
tion will be verified using thermocouples and an appropriate tional in early 2004. The use of consultants who have experi-
sterilization process cycle developed from these data. Steriliza- ence working with key equipment suppliers on complex large-
tion of the lyophilizer chamber and condenser will be demon- scale projects should allow the project to be completed as
strated using BIs to confirm a 106 probability of nonsterility. scheduled.
The lyophilizer is cleaned in place and the efficacy of the clean-
ing procedure will be verified. References
Utilities services validation. The new aseptic facility will have a 1. Cleanrooms and Associated Controlled Environments. Part 1: Classifi-
full complement of pharmaceutical utilities. These include water cation of Air Cleanliness (International Standards Organization, May
1999).
for injection, clean steam, pharmaceutical compressed air, in- 2. D. Meyer, “Developing a Barrier/Isolator Implementation Plan,” in
strument air, and compressed gasses. Each of these utility ser- Isolator Technology, C.M. Wagner and J.E. Akers, Eds. (Interpharm
vices and their related generation, storage, and distribution sys- Press, Buffalo Grove, IL. 1995), pp. 97–121.
tems will be validated to industry and compendial standards. 3. “PDA Technical Report No. 34: Design and Validation of Isolator Sys-
Testing will be conducted over a suitable time duration to tems for the Manufacturing and Testing of Health Care Products,”
J. Pharm. Sci. Technol. supplement to volume 55 (5) (2001).
demonstrate the long-term reliability of each utility system. In 4. J.M. Khoury, “Successfully Meeting FDA and Industry Expectations
addition, a concurrent validation program that will require in the Use of a High Speed Isolator—A Case Study,” in Proceedings of
more intensive testing and monitoring during the first 30 days the PDA Isolation Technology Conference (PDA, Irvine, California,
of operation will be implemented. Ongoing testing and moni- 2000).
toring programs will be designed to demonstrate ongoing con- 5. L.B. Coleman and G.D. Heffernan, “Dry-Heat Sterilization and
Depyrogenation,” in Validation of Pharmaceutical Processes—Sterile
trol and to ensure continuous compliance with industry and Products, F.J. Carleton and J.P. Agalloco, Eds. (Marcel Dekker, New
compendial quality requirements. York, 1999), pp. 483–526.
Validation of the background environment. The isolator network 6. J.P. Agalloco, “Steam Sterilization-in-Place,” in Validation of Pharma-
will be located in an ISO Class 8 surrounding environment as ceutical Processes—Sterile Products, F.J. Carleton and J.P. Agalloco, Eds.
required by current worldwide regulatory guidance. The sur- (Marcel Dekker, New York, 1999), pp. 451–482.
7. J. Akers, “PDA Technical Report No. 34: Harmonization and Key Tech-
rounding environment will be certified to comply with ISO Class nical Discussion Points,” in Proceedings of the PDA Isolator Technology
8 conditions under dynamic conditions. The room environment Conference (PDA, New Brunswick, New Jersey, May 2002).
will be the subject of an environmental monitoring performance 8. “PDA Technical Report No. 22: Process Simulation Testing for Asep-
qualification, and temperature and humidity will be controlled tically Filled Products, ” J. Pharm. Sci. Technol. 50 (S1) (1996). PT
in the range of 17–25 C and 50  10%, respectively (7).
Process simulation media fills. We anticipate that the typical lot
sizes filled in this system will range from a few hundred to
5000
vials. Media fills will be conducted to verify aseptic processing
performance over a representative range of container-closure
systems. Media fills will simulate ampul, vial, and lyophilized
vial filling processes. The media fills will consider all line
interventions and adjustments required during normal pro-
cessing. Trypticase soy broth media will be used for all media-
42 Pharmaceutical Technology OUTSOURCING RESOURCES 2003 www.phar mtech.com