6 BioPharm International
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Quality and Regulatory Sourcebook eBook March 2024 www.biopharminternational.com
Cell
and
Gene
Therapies
of the lifecycle phase. For clinical-phase and for com-
mercial-phase operations, the effectiveness of the
cleaning must be validated though swabbing and/or
contact plating for microbial growth. It may be effi-
cient to combine the line clearance procedure with
the cleaning one. It should be noted that traceability
means both chain of identity (COI) and chain of cus-
tody (COC). These must be implemented throughout
the entire lifecycle. Using validated automated bar-
code systems is standard as it is much more reliable
than any manual process.
Pre-sterilized consumable materials and reagents
are commonly used, and these are purchased ready
to use from qualified suppliers. As sterility assurance
is critical, so are the suppliers of these materials. The
PQS must have a supplier management procedure in
place that allows the risk-based selection, assess-
ment, and continuous qualification of suppliers, be-
ginning with clinical Phase I. Finding manufacturers
or suppliers of the required consumable materials
and reagents that are of appropriate quality, manu-
factured under suitably controlled conditions, and in
stable supply can be a challenge.
In analytical testing, as standard, the respective
pharmacopeial compendia must be complied with,
including microbial and for sterility testing, again
sta r t ing w it h product for clin ica l Phase I. Sma l l
batch sizes can mean that compendial requirements
for sterility test sample size cannot be complied with.
A solution may be to use rapid sterility testing meth-
ods, which have increasingly become the norm, and
are recommended for CGT products due to the speed
of obtaining results. Though these are non-compen-
dial methods, they can be used if appropriately vali-
dated for their intended use. With standard sterility
test methods, the results may not be available at the
time of product release (determined by the limited
shelf-life), suggesting t hat rapid steri lit y testing
methods may be the preferred method. It should
be noted that some regulator y agencies expect the
bioburden and endotoxins testing results to be part
of product release. As mentioned, non-compendial
methods must be fully validated, which in turn re-
quires a PQS that encompasses all the relevant re-
quired analytical method validation processes and
procedures. Of course, staff need to have the relevant
knowledge, training, and expertise to execute these
to GMP standards.
While qualif ied assays may be used for testing
patients during early development phases, samples
from pivotal clinical trials (clinical Phase III) need to
be tested using fully validated assays. Consideration
should be given to the maximum sample storage time
as developing some of the necessary assays (e.g., for
immunogenicity) may well take several years to fully
develop and validate.
A s k nowle d ge a nd pr oces s u nder s t a nd i ng i s
gained t hroughout t he lifec ycle, changes wi l l be
made to the process and the product formulation.
From a PQS perspective, a change management pro-
cess should be in place; the complexity of which will
likely increase closer to the product being commer-
cialized. That should meet the expected current GMP
requirements. Significant changes to optimize the
formulation and its presentation, such as changes
to the primar y packaging or the concentration of
excipients, should be made prior to the start of piv-
otal clinical Phase III studies. Making such changes
during Phase III is h igh risk and is discouraged.
In any case, as a minimum, analytical data will be
needed to demonstrate the comparability of the pre-
and post-change materials and to support the stabil-
ity of the post-change materials. Such changes may
also impact the trial design to demonstrate compa-
rability of immunogenicity.
Conclusion
Throughout early clinical development, the primary
focus is on clinical data and positive outcomes. What
is often lacking and frequently overlooked is the ap-
preciation of the resources needed to establish regu-
latory compliance. This can lead to the appropriate
evolution of qua lit y systems encompassing GMP
being neglected. This results in developers being
unprepared for and unsuccessful in regulatory ap-
proval, and significant delays to commercialization
of CGT.
Understanding how to apply phase-appropriate
GMP is crucial for achieving successful product ap-
proval with any regulatory agency and is critical to-
wards patients getting optimal access to their needed
therapies.
References
1. FDA. Approved Cellular and Gene Therapy Prod-
uc t s. F DA .gov (accessed Feb. 29, 2024). ht t ps://
w w w. f d a . g o v/ v a c c i n e s - b l o o d - b i o l o g i c s/c e l -
lu l a r-ge ne -t he r a p y-pr o duc t s/a p pr o ve d- c e l lu-
lar-and-gene-therapy-products
2. EM A. CAT Qua r terly High lights a nd Approved
ATMPs. ema.europa.eu. (accessed Feb. 29, 2024).
h t t p s:// w w w.e m a .e u r o p a .e u/e n/d o c u m e n t s/
r e p or t/c a t- q u a r t e rl y-h i g h l i g ht s-a p pr o ve d-a t-
mps-may-2023_en.pdf
3. www.clinicaltrials.gov
4. EC. Guidelines on Good Manufacturing Practice
Speci f ic to Adva nced T herapy Med ici na l Prod-
ucts. EudraLex Vol. 4. https://health.ec.europa.eu/
document/down load/ad33d9dd-03f0-4bef-af53-
21308ce2187d _en?f i lena me=2017_11 _ 22 _ g u ide-
lines_gmp_for_atmps.pdf
5. ICH. www.ich.org.
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