APR May/June 2023 - 55

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performed using a worst-case autoclave load that was determined to
be worst case based on the hardest to heat components we propose
as well as the load having the largest mass size. The autoclave is set
for 122°C for 12 minutes for production and 122°C for 11 minutes
for validation studies. Page 3 of the following document includes
results from three empty chamber heat distribution studies that were
performed in March 2022. Data supporting the heat distribution
and penetration of the worst-case load with biological indictors
is provided beginning on page 10. This data was compiled from
December 2022-Feburary 2023. The acceptance criteria for each study
are included prior to the data tables and all data met the criteria. The
requalification program is described in detail on page 25 and includes
an annual HP/BI run of the worst-case load. "
It may not be obvious to the applicant to include this type of
introductory summary, but the value is enormous to the assessor as
it helps them understand your overall process, identify exactly what
the validation study comprises, and provides them with insight into
your thought process when establishing your validation/qualification
program. Without a summary, the assessor must work backwards from
reading the data and hopefully piece together an overall picture of the
validation program. The latter typically results in numerous clarifying
questions being sent in an information request. FDA reviewers are
highly trained scientists who are trained and equipped to assess a
range of validation/qualification scenarios; however, the assessor does
not have infinite time to do this, and summary statements can assist in
making the assessment more efficient.
Continuing with the idea of clarity in your application, most applications
contain references to drug master files (DMF). The DMF might contain
information ranging in complexity from the depyrogenation of a
single component to all the supporting information for a contract
manufacturing facility. If you can include all data for an application
in the A/NDA submission itself, that is ideal; however, we understand
that due to confidentiality issues this might not be possible. If a
DMF reference is needed, you should plan to provide a clear and
concise summary of what is being referenced. Additionally, stating
the submission date and DMF volume that the information is in
can significantly expedite assessment. Simply providing a letter of
authorization to a DMF leaves the assessor potentially searching
through hundreds of files trying to find relevant data to support your
proposals. Specifically citing a date and volume of the submission
with a summary of what type of data is being referenced will allow
the assessor to immediately identify what you are referencing while
minimizing additional information requests asking for the necessary
data or the location of this data within the DMF.
Pivoting away from the role of application clarity and its role in
expediting the application assessment, the following sections
deal with technical issues that are commonly encountered in the
assessment of A/NDAs. Numerous DMA assessors with many years
of experience were queried asking for common deficiencies that
they routinely observe in A/NDA submissions. The resulting items are
presented below.
Bulk Solution Bioburden Monitoring
Bulk solutions prior to filtration are not typically sterile and should
have microbial controls to ensure that they maintain appropriate
microbiological quality throughout the manufacturing process. To
achieve this, we request that firms implement a routine bulk bioburden
sampling program; however, we often see that this sampling step
is performed after a 0.45µm or 0.22µm filtration step. Bioburden
sampling after filtration defeats the purpose of sampling the bulk
solution and does not allow for an understanding of the microbial
load of the nonsterile bulk. Even sampling after a 0.45µm filter, while
not a sterilizing filter, defeats the purpose as this type of filter can
still remove a majority of organisms. Sampling and monitoring of
the bulk solution should be performed prior to any filtration step, as
this allows for a better understanding of its microbial composition. It
is worth noting that any excessive growth in a bulk solution prior to
filtration could allow for microbial metabolites or endotoxins to pass
through the filters and could cause quality issues in the subsequent
downstream processes.
Biological Indicator Incubation
For sterilization validation studies where biological indicators (BI) are
used to support a sterility assurance of 10-6
, the incubation time of the
BI should be seven days (USP<55>, ISO 11138). There has been some
confusion within the pharmaceutical industry as well as from the BI
manufacturers regarding the conditions under which it is appropriate
to reduce the typical seven day incubation to 24 hours. This comes from
an FDA guidance1
published by the Center for Devices and Radiologic
Health (not CDER) that is specific for healthcare facility sterilization
and treats the healthcare facility sterilizer as a medical device. The
guidance discusses the acceptability of 97% of positive indicators
showing appropriate growth at the 24-hour incubation period versus
the full seven day period. While we appreciate the utility of this reduced
incubation time for healthcare sterilization, this guidance was not
intended to address a pharmaceutical manufacturing facility that
produces sterile injectable drug products. The expectation for BIs to
support sterilization validation studies is that a seven day incubation
period is observed.
Pooling of Endotoxins Samples
Finished product bacterial endotoxins testing is critical to ensure that
a high-quality pharmaceutical product is released. The most common
test observed in A/NDA submissions is the USP<85> gel clot test. This
test requires the consideration of a maximum valid dilution (MVD)
which accounts for the endotoxins limit, the sensitivity of the test and
the concentration of the drug product. The maximum valid dilution
specifies the limit that the drug product can be diluted while still
giving a valid result. We also see that many times in testing, a drug
product vial is pooled with other vials to allow for one test to screen
multiple vials; however, applicants will often forget to adjust the MVD
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