Single-use systems (SUS) come with
increasingly complex challenges that
are often misconceived since industry is
still in the early stages of adopting this
technology. One of the more complicated
SUS aspects is sterilization validation.
A successful validation requires strong
collaboration early in the manufacturing
process design phase among all parties
involved.
The pharma firm, the SUS manufacturer,
the contract sterilization vendor and the
contract microbiology laboratory each
play a part within the validation process.
This partnership ensures shared understanding
between all four players on the
inherent complexity, uncertainty and
resource demand in SUS design, validation
and commercial manufacturing.
Additionally, common misconceptions,
false assumptions and veiled communication
between the pharma firm and the
SUS manufacturer must be highlighted,
brought into the open and addressed.
Such open collaboration cultivates invaluable
knowledge transfer, greatly minimizing
risk of SUS failures later on.
One of the most important outputs of this
open collaboration can be found in an effective
validation approach to the sterilization
of SUS using gamma irradiation.
No Clear Guidance for Sterilization
Validation
The complexity of SUS sterilization validation
and associated process controls are
commonly underestimated. Contributing
to this is a lack of relevant regulation.
AAMI/ANSI/ISO 11137:2006 and ISO
11737:2006, ?Sterilization of medical devices
– Microbiological methods, are the only two
standards available today for sterilization
of SUS in pharma manufacturing. The fact
that these two standards (and, ostensibly,
any other guidances published on irradiation
validation) were developed solely for
medical devices is the main factor that
complicates applying them to SUS. Plus,
these standards generally cover risk to
patients from a device. In contrast, SUS
sterilization validation is intended for decontamination
and sterilization of product/
process solution equipment contact surfaces—
which do not come into direct contact
with patients (i.e., the risk is different).
An SUS may be risk-assessed for lower
sterility assurance levels (SALs) with
lower lethality (e.g., 10–3 SAL) than the
conventional 10–6 SAL. This risk-based
determination can be made by assessing
the specific step(s) in a bioprocess to
determine if an SUS is used at a point in
the process stream where there are downstream
controls on sterility, such as sterilizing
filtration. Process contact surfaces
that have undergone the final 0.2 μm
sterilizing filtration for drug product aseptic
fill are the only ones that technically
require 10–6 SAL. It is important for SUS
end users to recognize that application of
10–6 SAL across all components of the
bioprocess may not be appropriate from
a unit operation contamination control
strategy perspective and can lead to risks that are not so apparent. In reality, lower
SALs, or statistical bioburden grouping
strategies and controls for unit operations
may prove a better risk-based approach.
There is additional benefit with this
approach. Reduced gamma radiation dosages
also lower SUS material effects that
can impact drug product quality. There
is a direct relationship between radiation
dose levels/dose rate, and changes to SUS
polymer chemical structure perspective. In
order to achieve higher gamma irradiation
dosing, a longer cycle time is required.
Longer irradiation cycle times can foster
increased gamma radiation-induced
chemical modifications, and worsening
of leachables/ extractables from the SUS.
Ionization and accompanying molecular
excitation of SUS materials differs across
classes of polymers, with some exhibiting
higher resistance to irradiation-induced
modifications than others. All polymers
are affected by gamma irradiation to some
extent.
For SUS, the basis of a sterilization validation
program is the development of a
simulated product master (SPM)—commonly
referred to as a “monster assembly.”
SPMs are designed to provide a model
of worst-case materials, components,
connections and processing used in the
manufacture of all commercially-produced
SUS assemblies at an SUS manufacturing
plant. To fully simulate exposure to
the same manufacturing conditions, these
SPM “monsters” should be manufactured
using the same processes as commercially
produced SUS solutions.
The suggestion here is similar to process
simulation media fills performed in the
pharmaceutical industry. As the SUS
manufacturer’s portfolio of sterile SUS
grows, the SPMs should routinely be evaluated
to determine if they are still a good
model of new products in the portfolio.
If not, the SPMs must be modified or the
sterilization validation program must be
revised (i.e., with a new, more monstrous
SPM, or a validation customized to the
new SUS goods). This simulated master
must be applied when establishing the
minimum radiation dose specification,
and for subsequent quarterly dose audits
(revalidations). Assessing the attributes
and criteria of devices for the purpose of
creating a simulated master for validation
that is feasible in application can be quite
difficult when the customization and
complexity demands grow.
Validation Requires Team Approach
As mentioned earlier, the pharmaceutical
manufacturer, the SUS manufacturer,
the contract sterilization vendor and the
contract microbiology laboratory each
own a piece of the activity within this
sterilization validation process. The regulatory
onus to ensure compliance and final
product quality, however, remains the
responsibility of the pharmaceutical firm.
The perspectives and know-how of these
four parties is based on their function
within the supply chain.
This can become even more complex
when distributors enter this mix between
the SUS manufacturer and the end user,
possibly resulting in less transparency and
increased risk within the supply chain that
is not understood. Among all these parties,
there is often a lack of overall understanding
on the necessary control scheme,
the science, and the compliance needed to
effectively maintain the validated state of
the SUS. For example:
- The contract sterilization vendor is
accustomed to decades-old processing
to meet medical device manufacturers’
needs, which are very different than
SUS manufacturer needs. For example:
- the variability of different product
codes for medical devices is low
- the volumes for a device manufacturer
are relatively high compared
to SUS
- the variability of packaging
configurations is relatively low in
medical device
- the density is relatively uniform for
medical devices compared to SUS
density nonuniformity—critical
as variability of densities directly
influences dose delivery and distribution
variability
- Contract microbiology labs are commonly
unaware of the significant risks
the pharma industry faces in the event of
sterility false positive (i.e., invalid sterility
failure). They must have the infrastructure
and technical capabilities to assess
these large and multimaterial assemblies
without contaminating them. Many
test labs are unwilling to test very large
systems when they understand the risk
associated with the testing. They must
have the capability to develop appropriate
test methods and validate those test
methods. The testing costs can become
significant due to the time required to
develop and validate test methods and
perform routine testing of these “monstrous”
assemblies. Thus, selection of a
reputable, competent contract microbiology
test lab is imperative.
- Too many SUS manufacturers do not
understand the compliance requirements
within the AAMI/ISO standards,
and not all SUS manufacturers
have knowledge on the material science
or the necessary validation expertise.
SUS manufacturers often do not
understand fully how their SUS will be
used in the biopharmaceutical process.
SUS manufacturers commonly do not
have technical experts capable of properly
assessing the capabilities of the
contract microbiology labs, without
which it is difficult to recognize gaps
that put the SUS manufacture and/or
sterilization process at risk.
- The pharmaceutical firm is often unfamiliar
with the AAMI/ISO standard
for sterilization of SUS, the significant
lack of and/or gaps in the sterilization
validation at many SUS manufacturers
and the costs and time associated with
maintaining a compliant sterilization
validation program. The desire
to choose the lowest cost vendor can
often outweigh the value of choosing
the most qualified supplier. This is
short-sighted when considering the
enormous risk associated with the
product supplied via sterile SUS.
Playbook for Handling Complexity
The ever-increasing complexity of SUS
designs presents another challenge. This
scenario is on the rise due to manufacturers’
desires to replace more of their fixed
process equipment with disposable SUS.
Large and unwieldy assemblies with
dozens of feet of tubing, multiple filters,
multiple connectors, needles and containers
are becoming increasingly prevalent.
End users are increasingly seeking a high
degree of customization in designs, leading
to complexity in the manufacturing,
packaging, shipping and validation.
How does one assess an SAL on something
like Figure 1? How does a testing lab even
go about executing sterility testing on such
a “monster?” What could the total bioburden
look like on an assembly like this?
Consider the following example. A biopharma
company sought an SUS design
to take product from final formulation to
final fill. The company did not want any
aseptic connections in their process suite
and requested a design containing dozens
of feet of tubing along with multiple connectors
and filters, needles, containers, etc.
Figure 1 Example of a Complex SUS Assembly
When the SUS manufacturer validated the
SUS, the bioburden results were >3000
cfu on a total immersion of the system.
These high bioburden levels were truly
“monstrous.” Naturally, the SUS provider
was resistant to putting their entire
customer-base at risk by revising their
SPM to include all the elements of this
new assembly.
This presented three options for the SUS
provider and the biopharm firm: 1) break
up the assembly into three sections and
add aseptic quick connectors; 2) assess
the risk within the biopharma process
stream and determine if a specific section
of the assembly is upstream of sterility
controls (e.g., sterile filtration), thus, only
the downstream section of the assembly
may require 10-6 SAL; and, 3) consider if
a 10-6 SAL exclusively on the fluid path
of the assembly is acceptable since there
is typically significantly lower bioburden
on the fluid path of SUS. The biopharma
company ultimately determined that their
process could allow for a sterile label claim
only on the fluid path of the assembly.
There is also a time and cost factor that
must be considered. The validation
approach includes far more than just irradiation
of the assembly. So what is the
requirement within the current AAMI/
ISO 11137:2006 guidance? The guidance
covers the following areas with regard to a
validated sterilization program:
- Determination of material radiation
compatibility and resistance;
- Determination of the average bioburden
for a specific product on a statistically
representative number of parts;
- Exposure to a minimal radiation dose
statistically calculated to deliver 10–2
SAL (termed a sublethal dose) on a
representative number of parts;
- Bioburden evaluation and control on
individual components within the
SUS—often these can be purchased
components which require robust supplier
oversight;
- Validated test methods at the testing
laboratory using representative samples
of the SUS;
- Product dose levels validated as sterile
are subject to routine “dose audits”
involving bioburden testing, sublethal
dose delivery and sterility testing;
- Control of the SUS manufacturing
environment (e.g., cleanroom environment,
viable/nonviable environmental
monitoring, proper gowning); and,
- aluation of product density, product
packaging shielding effects, and irradiator
product load configuration.
When considering the risks as they exist
today, consider the increased demand
for SUS in the future. Industry groups
including PDA (see PDA Technical Report
No. 66: Application of Single-Use Systems
in Pharmaceutical Manufacturing) are
beginning a dialog on this topic. It will be
increasingly important for there to be risk-based
standards and guidance documents
specific to SUS that address the needs and
knowledge of both SUS providers and
pharma. In the meantime, to ensure a
sterile SUS, it is imperative the four types
of partners discussed herein understand
each other’s needs and limitations to
achieve the ultimate goal of ensuring supply
of safe and effective products.
About the Author
Polly Hanff is the Global
Regulatory Affairs and Quality
Director at Saint-Gobain
Performance Plastics with
overall responsibility to assure
the quality and compliance of
single-use systems manufactured
for the pharma industry.