PROCESS
SIMULATION TEST PROCEDURES
General
Comments:
The
media fill should emulate the regular product fill situation in terms of
equipment, processes, personnel involved and time taken for filling as well as
for holding.
Where
filling takes place over extended periods, i.e. longer than 24 hours, the
process simulation test should extend over the whole of the standard filling
period. In order to prevent excessively high numbers of units being filled it
is usually acceptable to just run the machine for a reasonable time, if the
validity of the simulation is not diminished by this procedure.
It
should be considered that inert gases will prevent the growth of aerobic
microorganisms. Therefore for process simulations sterile filtered air should
be used instead of inert gases, also for breaking a vacuum. Where anaerobes are
detected in the environmental monitoring or sterility testing, the use of an
inert gas should be considered for a process simulation, as inert gas is
supporting the growth of anaerobes.
Before
enumerating the different process simulation test procedures some preliminary
explanations are necessary for the preparation of liquid media as it is used
for the majority of the process simulation tests. Where a liquid nutrient medium
is used it should be prepared in a similar manner to the product. The medium
should be dissolved in Water for Injection in a standard manufacturing vessel.
If heat is required to dissolve it then only minimal heat should be used. The
pH of the medium should be measured and, if necessary, adjusted to bring it
into the required range. The medium should be aseptically filtered into an
aseptic holding vessel using the normal production filter and processing
procedure. In justified cases it may be also acceptable to sterilise the media.
All aseptic holding vessels should be covered by a process simulation test on a
regular basis unless a validated, pressure hold or vacuum hold test is
routinely performed.
The
following chapter illustrates the test procedures for the various simulation
tests for aseptically produced solutions, lyophiles, suspensions, ointments and
powders and summarises the considerations to be made.
Liquid Products
Vial Products
The
liquid growth medium for the simulation test is prepared as above and kept in a
sterile holding vessel for the maximum permitted holding time before starting
the simulation test. If the bulk solution is stored under refrigerated conditions
during the holding time then this should also be performed for the medium.
Vials and closures should be prepared as in regular production.
Sterile Products in Plastic Containers
Ear and
eye drops are typically marketed in plastic containers. Containers, inserts,
closures and where applicable over seals are washed and sterilized as in
regular production. Instead of sterilization with heat, irradiation or ethylene
oxide are used.
Whilst
clear plastic containers are frequently used for process simulation trials, the
plastic is usually slightly opaque and thus hinders identification of
contaminated units that show only a slight haze. In such case examination under
natural or room lighting would not suffice. Where opaque containers are used
for process simulation trials the whole contents should be removed for
examination.
Ampoule Products
Open or
closed ampoule types may be used. They should be sterilized by dry heat and
afterwards used in the simulation test as per the regular production run.
Ampoules
should be prepared as in regular production.
Injectable Powder Products
There
are two possibilities for simulation of this process. Either by filling a
sterilised liquid growth medium into the sterile container or adding a powder
(inert or growth medium) before or after a sterile diluent (WFI or growth
medium). Inert materials commonly used include: polyethylene glycol 8000 and
carboxymethyl cellulose. These materials are usually sterilised by irradiation.
Suspension Products
This
procedure is comparable to the filling of liquid products, except for the
process step of maintaining suspension of the ingredients. The stirring or
recirculation should be part of the simulation. If aseptic additions are made
to the bulk solution these should be simulated by the use of inert sterile
liquids/powders.
Freeze Dried (Lyophilised) Products
Crystallisation
of the medium should be prevented because it may reduce the likelihood of
recovery of organisms.
Two
simulation methods are commonly used. In the first one a dilute medium is
subject to a cycle that removes water until a determined medium strength is
obtained, but is not subject to freezing. The second method uses full strength
medium and requires only a partial vacuum be drawn whilst the chamber should be
kept at ambient temperature. There is a risk that the medium may boil over and
contaminate the chamber unless conditions are tightly controlled. The absence
of boiling under the defined cycle conditions should be confirmed.
Semi-Solid Products (e.g. sterile ointments)
For
this simulation test the liquid growth medium is thickened to the appropriate
viscosity, used as in the routine production procedure. Suitable thickening
agents are agar and carboxymethyl cellulose. Other agents would need to be
validated with regard to lack of their bacteriostatic and fungi static
properties. Metal and plastic ointment tubes prevent the examination of the
medium in-situ. Usually the whole content of the tube should be examined and
this is usually achieved by squeezing the contents into a plate (petri dish),
and after whirling it is examined for turbidity and fungal colonies under
defined light conditions or by performing a sterility test. If properly
validated, an alternative method for detection of contamination of semi-solid
products could be the use of media which changes color in the presence of
contamination.
Clinical Trials Materials and Small Batch Size Products
As processes
for smaller quantities (less than 3000 units) do not allow an interpretation
according to chapter 5 of these Recommendations, any presence of microbial
contamination should be regarded as an alert limit. Monitoring and test
conditions, like incubation or media selection remain the same as for
commercial production runs.
The
size of media fills for small batch size products should at least equal the
number of containers filled for the commercial product.
Biological and Biotechnology Products
The
manufacture of these products varies, such that there is not one single
process. It may be more practical to validate the various segments of the
process individually. The frequency of the revalidation should relate to the
one of regular, commercial production.
Sterile Bulk Pharmaceuticals
Whenever
possible a growth medium should be used and the process should be simulated as
closely as possible to the normal route of manufacturing the sterile bulk drug
substance.
The
aseptic manufacture of sterile bulk drug substances is a difficult process,
which may have numerous individual segments that need to be validated. The
possibility of microbial ingress into the system has to be considered after
each step of the routine production.
The
validation may include segments, where the use of growth media is not feasible.
Author: Mahender Nagaraju
Source: PIC/S Guidelines
www.gmpviolations.com
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