APR Sept/Oct 2023 - 111

« MICROBIOLOGY
important to ensure they do not inhibit the growth of microorganisms.
( " Surrogate " is not defined in the glossary.)
In paragraph 9.33, Annex 1 states that the APS should imitate the
routine aseptic manufacturing process as closely as possible and
include all the critical manufacturing steps. While this is not a new
requirement, the following steps are new:
* The scope of the APS should include all aseptic operations after
the sterilization and decontamination of materials to the point
where the containers are sealed.
*
Non-filterable products should have additional or other aseptic
steps considered.
* Process air should be used instead of inert gas to promote
the growth of microorganisms. An exception to this is when
anaerobes have been isolated from these systems, and APS is
performed specifically to detect anaerobes in these systems.
* Surrogate materials can be used in place of sterile powders in
the same containers.
*
Individual simulation for unit operations should be avoided
unless supported by documented justification, ensuring all the
unit operations APS add up to cover the whole process.
Lyophilization
The APS requirement for lyophilization is also introduced in this
new Annex 1. The main consideration is to simulate all aspects of
the lyophilization process including filling and transport of vials.
There are some exceptions where the simulation process may have
an impact on the recovery of the microorganisms, such as using
process air instead of nitrogen during vacuum break, or causing
boiling-over or freezing of the media. Elements to consider in APS
design include the maximum sterile hold time, i.e., duration from
end of sterilization to use of lyophilizer, and the maximum hold
time from filtration to lyophilization.
Some examples of worst-case challenges are also mentioned. These
include loading the largest number of trays, and maximum duration of
chamber door opening where the chamber interior is exposed to the
clean-room environment.
An important requirement in the new Annex 1 is 8.123. " Lyophilizers
and associated product transfer and loading/unloading areas
should be designed to minimize operator intervention as far
as possible. The frequency of lyophilizer sterilization should be
determined based on the design and risks
related to system
contamination during use. Lyophilizers that are manually loaded
or unloaded with no barrier technology separation should be
sterilized before each load. For lyophilizers loaded and unloaded
by automated systems or protected by closed barrier systems, the
frequency of sterilization should be justified and documented as
part of the CCS [Contamination Control Strategy]. "
This requirement seems to indicate a preference for automated
loading and unloading, and/or with the loading/unloading equipment
protected with barrier isolation, under which situations the frequency
of lyophilizer sterilization can be justified and documented, as opposed
to manual loading/unloading situations where the lyophilizers must
be sterilized before each use. The additional delay permitted for
introduction of this requirement (25 August 2024) seems to indicate
that mechanical modification within the clean room and re-validation
via media simulation is expected (which may be incorporated during
an annual shutdown).
Interventions
Assessing the contamination risk of various types of interventions is
an important objective of APS. The new Annex 1 now requires the
inclusion of various aseptic manipulations, interventions, and other
worst-case scenarios in APS. Aseptic manipulations must include
aseptic setup of the filling machine. The key consideration here is to
simulate interventions occurring during the routine aseptic process
as closely as possible during APS. An appropriate practice would be
to review all interventions occurring during processing, e.g., every
six months or each year, and add any new interventions into the APS
Protocol. Similar interventions may be grouped together, and worstcase
conditions must be selected/justified in the APS protocol. The
new Annex 1 also mentions frequency, which means if an intervention
occurs frequently such as topping up a stopper bowl, then it should be
performed at similar frequency during APS; changing filling needles
is not performed on a regular basis, so its frequency in APS should be
less than topping up the stopper bowl. The inclusion and frequency
of interventions should also be based on risk assessment - higher
risk interventions that pose risks to the sterility of products must be
included and performed.
Paragraph 9.35 states, " APS should not be used to justify practices
that pose unnecessary contamination risks. " This point has been
mentioned numerous times in the past by various regulators and
Quality Assurance groups. It is not justifiable to include interventions
in the APS that may increase the risk of contamination, in an attempt
to validate such practices. An example would be the opening of a
Restricted Access Barrier System (RABS) to perform major repair work.
Considerations for APS Plan
In the new Annex 1, thorough details are provided to develop the APS
plan, and the following considerations are explored:
1. Identification of worst-case conditions and variables for APS.
An assessment needs to be performed to identify and select
process variables and worst-case conditions based on the
impact to the process. An example of a worst-case condition
would be the vial size with the largest opening of the
vials, where the exposure to the environment is maximum.
Slowest line speed also presents a higher risk as the vials are
exposed to the environment for the longest duration.
www.americanpharmaceuticalreview.com |
| 111
»
http://www.americanpharmaceuticalreview.com
APR Sept/Oct 2023

Table of Contents for the Digital Edition of APR Sept/Oct 2023
