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The Aseptic Core.

Ed White, Coordinator ]
Aseptic Process Simulation
Ed White

The Aseptic Core discusses scientific and regulatory (SCDM), although other media may be used with
aspects of aseptic processing, with an emphasis on suitable growth promotion.
aseptic formulation and filling. This column has been
developed with the intention of providing practical INTRODUCTION
advice to professionals involved in the qualification Aseptic process simulation is one of the last steps in quali-
of aseptic processes and the myriad support processes fication of an aseptic processing facility (typically just
involved. The primary objective for this column: prior to conformance runs). Aseptic process simulations
Useful information. are also a key element of ongoing process validation of
Reader comments, questions, and suggestions are an operational aseptic processing facility.
needed to help us meet our objective for this column. This article briefly discusses the definition of an
Suggestions for future discussion topics are welcomed. aseptic process simulation; describes how to set up an
Discussion topics and case studies related to aseptic aseptic process simulation program; gives some points
processing submitted by readers are invited. Please to consider, and provides typical examples.
email your suggestions to shaigney@advanstar.com.
WHAT IS ASEPTIC PROCESS SIMULATION?
KEY POINTS Aseptic process simulation is a method to determine if a
The following key points are discussed in this article: purportedly aseptic process really is aseptic. In an aseptic
Aseptic process simulation (media fills) is the lynch- process simulation, the aseptic process (or a portion of
pin of any qualification of an aseptic facility the aseptic process) is performed using growth media
Aseptic process simulations should be carefully instead of the products or chemicals in the process being
planned to ensure the length of the simulation and simulated. The growth media from the simulation is then
the number of manipulations performed during the sterility tested. If it is sterile, it can be assumed that the
fill are representative of the actual process process was performed aseptically. If not, then the source
A matrix or bracketing approach may be taken for of the contamination should be investigated, corrective
a facility or filling line where multiple products or and preventive actions should be made, and the aseptic
dosage forms are filled or processed process simulation should be repeated.
For a new facility or process, it is advisable to per-
form a few practice fills before performing an aseptic Media Fills
process simulation The most common aseptic process simulation is the
Aseptic process simulations need their own batch media fill. In a media fill, a representative number of
records that mimic the process being simulated and dosage units, typically >5,000 units, are filled, sealed,
include details such as number and type of aseptic and placed in one or more incubators where they are
manipulations, number of personnel, length of incubated for 14 days at the proper temperature(s) to
run, line speed, etc. promote microbial growth (typically 7 days at 2025C,
The growth medium used for aseptic process simu- followed by 7 days at 3035C). The filled units are then
lations is typically soybean casein digest medium inspected for microbial growth.

[
For more Author ABOUT THE AUTHOR
information, Ed White is a Senior Principal Validation Engineer at Baxter Healthcare, Thousand Oaks, CA.
go to He may be reached by e-mail at ed_white@baxter.com.
gxpandjvt.com/bios

gxpandjv t.com Journal of Validation T echnology [Winter 2010] 39


The Aseptic Core.

If all units are negative for growth, a growth promo- Line configuration
tion study is performed on the media. If the growth Operator interventions in the process (e.g.,
promotion passes, the media fill is successful. If the removal of tipped vials from a filling line,
growth promotion study fails, the failure must be inves- weight checks, manual addition of a sterilized
tigated and the media fill repeated. If there are positive powder to a sterile suspension formulation,
units in the media fill vials, the source of the contami- aseptic sampling, etc.)
nation must be investigated, corrective and preventive Any special conditions, such as lyophilization,
actions made, and the media fills repeated. product recirculation for suspensions, etc.
Determining the frequency and number
Other Aseptic Process Simulations of runs for each aseptic process simula-
Some of the other processes where aseptic process simu- tion. Some aseptic process simulations may be
lation may be performed include the following: performed only as a verification activity dur-
Aseptic compounding ing commissioning of new equipment, such as
Aseptic crystallization bioreactors or fermenters. Most aseptic process
Aseptic precipitation simulations, however, will be performed on a
Bioreactor and fermenter charge and inoculation routine, usually semi-annual basis. During initial
Other aseptic processes in the biotech and qualification during start-up of a facility, you will
parenteral industries. perform three media fills before proceeding to
the process validation or conformance lot phase
Each of these processes has unique requirements that of the start-up.
make performing an aseptic process simulation useful.  Something that should be considered during
this stage is if you are going to use a bracket-
SETTING UP AN ASEPTIC PROCESS ing or matrix approach for your aseptic process
SIMULATION PROGRAM simulation program. For an aseptic filling pro-
Aseptic process simulation should be part of the over- cess, for example, you would rotate factors such
all process validation program for a new facility. This as line speeds, vial sizes, lyophilized products,
program should be part of the facility master plan and other processes that might prove worse
or a separate aseptic processing procedure. Steps to case. Processes that are not worse case, such
setting up an aseptic process simulation program as an intermediate vial size between largest and
include the following: smallest vial might be covered by media fills
Defining the aseptic processes. Review your for the largest and smallest vials in the routine
manufacturing processes to determine the number manufacturing schedule.
of aseptic processes and the number of aseptic Developing batch records or process
unit operations. instructions for each aseptic process
Performing a risk assessment on each asep- simulation. Each aseptic process simulation
tic process. Perform a high level risk assessment needs detailed instructions on how to perform
for each aseptic process to determine its effect on it. This is usually accomplished by a specialized
patient safety and product quality. Separate the batch record or manufacturing instruction for the
processes that could result in a non-sterile product, aseptic process. A good aseptic batch record will
such as filling of a final product, from processes include the number and type of aseptic manipula-
that may cause loss of product but little or no risk tions observed in the manufacturing process, line
to patients, such as addition of growth factors or speeds, duration of runs, the number of people
nutrients to a bioreactor. in the aseptic processing area for each run, envi-
Evaluating each process for key control ronmental monitoring during the run, growth
points and key factors that could present a media used for process simulation, incubation
risk of microbial contamination of the prod- times, and temperature, etc.
uct. Items to consider include the following: Developing a schedule for aseptic process
Length of the process simulations. Aseptic simulations are required
Number of people involved in the process on a semi-annual basis for critical aseptic pro-
Shift changes or breaks involved in the process cesses such as aseptic filling. These should be
Line speeds (if applicable) included in the routine production schedule so
40 Journal of Validation T echnology [Winter 2010] iv thome.com
Ed White, Coordinator.

that they are considered part of the routine manu- High Speed Filling Line
facturing process. When scheduling an aseptic Key items to consider for a high-speed filling line are
process simulation, ensure that factors such as line the run size and run length. A high-speed filling line
speed, vial size, aseptic manipulations, etc., are may run 200,000 vials over two shifts. Running 5,000
scheduled into the aseptic process simulation so vials over a 10- to 20-minute period is not representa-
that any bracketing or matrix approach is covered tive of the process. Consider increasing the run size to
on a routine basis. something more representative of the process. Also,
increase the run length to the actual run length by
PERFORMING AN ASEPTIC PROCESS running the line in short bursts followed by lengthy
SIMULATION downtimes. For example, for a two-shift operation
An aseptic process simulation should simulate the running 200,000 vials a day, you might fill 5,000 vials
original process as closely as possible, given the obvi- at the beginning of the run, 5,000 vials before shift
ous constraints imposed by the use of media instead change, 5,000 vials after shift change, and 5,000 vials
of actual product for the simulation. at the end of the day, for a total of 20,000 vials. Typi-
The first step in an aseptic process simulation is cal aseptic manipulations such as removing tipped
preparing the growth media. This is typically soybean vials, weight checks, line clearance, etc., would be
casein digest medium (SCDM), although other media included throughout the 20,000 vial fill.
such as fluid thioglycollate broth, peptone broth, etc.,
may be used in special cases. In any case, you will Lyophilized Product
have to perform growth promotion studies on your A lyophilized product fill will typically be smaller,
growth media with your environmental isolates as due to lyophilizer capacity. A 5,000-vial fill is prob-
well as standard growth promotion organisms. This ably a sufficient size for a media fill. For a lyophi-
media is used for the remainder of the simulation to lizer fill, you would simulate a normal filling pro-
represent the product being processed. The media is cess, including partial insertion of the stoppers, and
typically compounded, then sterilized by sterile filtra- load the vials onto lyophilizer shelves maintained
tion or moist heat sterilization, as applicable. at room temperature (2025C). When all of the
Equipment used in the aseptic process simulation vials are filled, the lyophilizer would be sealed, and
should be sterilized or sanitized as in the normal a partial vacuum would be pulled on the lyophilizer.
process; all ancillary items should also be sterilized The vacuum would then be released, and the normal
or sanitized per the normal process. transfer and capping processes would be simulated.
Once the media, equipment, and ancillary items Routine considerations such as number of aseptic
are prepared, the operators perform the process simu- manipulations, shift changes, line speeds, etc. should
lation as closely as possible to the original process, be included in an aseptic process simulation for a
including the aseptic techniques, routine manipula- lyophilized product.
tions, number of personnel, line speeds, length of
run, etc. Low Speed Filling Process
The media-containing vials, ampoules, syringes, One of the considerations in a low speed filling pro-
etc. or bulk media are collected and incubated for cess is that the run size may be less than 5,000 units.
14 days at an appropriate temperature (typically 7 If feasible, I recommend performing a 5,000 unit fill.
days at 20-25C and 7 days at 3035C). If there If not practical, fill the maximum batch size. You
is no growth, the media are tested for growth pro- should have a rationale for filling less than 5,000
motion using standard test organisms plus routine units built into your media fill procedure, explaining
environmental organisms. On successful growth the reason for the smaller size fills and any mitigat-
promotion, the aseptic process simulation can be ing actions. It is important to have a justification in
considered successful. writing, as the regulatory agencies will ask about your
media fill run size.
ASEPTIC PROCESS SIMULATION
EXAMPLES Bioreactors And Fermenters
The following sections highlight some examples of This type of aseptic process simulation is usually only
aseptic process simulation. performed during commissioning of a new bioreactor
or fermenter, or if a major change is made to a bioreac-
gxpandjv t.com Journal of Validation T echnology [Winter 2010] 41
The Aseptic Core.

tor or fermenter. This type of aseptic process simu- VALIDATION IMPLICATIONS


lation is not required in any regulation or guideline Aseptic process simulation is a critical validation
that I am aware of, but I consider it a good practice procedure that is performed before implementing
before committing the bioreactor to processing prod- a new aseptically-manufactured product or aseptic
uct. In this simulation, you perform the operations process. Careful consideration and design of an
such as transfer of the contents of a seed bioreactor aseptic process simulation is required for successful
to the main bioreactor, aseptic sampling of the bio- implementation.
reactor, transfer of growth factors or media, transfer
of the cell broth to a harvest tank, etc. The media
is incubated for a 14-day period and then tested for GENERAL REFERENCES
sterility. In some cases, the entire media batch may FDA, Guidance for Industry: Sterile Drug Products Produced
be filtered and the filter tested for sterility per rou- by Aseptic ProcessingCurrent Good Manufacturing Practice,
tine sterility test procedures. Because this is usually 2004.
a commissioning and verification test, there is more European Commission, Enterprise and Industry Direc-
leeway in how the test is performed than with aseptic torate-General. EudraLexThe Rules Governing Medicinal
simulation of filling processes. In any case, the objec- Products in the European UnionVolume 4EU Guidelines
tive of this simulation (i.e., final shakedown before to Good Manufacturing PracticeMedicinal Products
committing product, diagnostic for fermenter and for Human and Veterinary Use, Annex 1: Manufac-
bioreactor contamination investigation, etc.) should ture of Sterile Medicinal Products (corrected version),
be carefully considered when you are designing the 2008. JVT
process simulation.

42 Journal of Validation T echnology [Winter 2010] iv thome.com