well as their associated training needs. It will also provide valuable
information around personnel requirements to determine operations
Closure definition and investigation are a critical aspect of system
design. Process closure analysis is more detailed and clearly a focus
of regulatory scrutiny. Managing the logistics of the numerous tube
sets introduces many aspects of “spaghetti management” that will
require a different level of project management and engineering in
order to bring value and efficiency, not to mention compliance with
many Environmental Health and Safety and cGMP regulations. The
focus must be on operational efficiency.
IDENTIFICATION OF TRAINING NEEDS
Single-use systems and disposable components do have unique
elements associated with their inspection, assembly, and operation.
Training personnel in the proper methods of handling SUS
components, identification of potential defects in materials and
assemblies, set-up for testing to prove integrity, and verification of
assembly configuration and closure will likely require development
of a new set of standard operating procedures (SOPs) and protocols.
The information needed for these will be developed from both
internal and external source information, process development
studies, pilot-plant and clinical operations, and vendor data.
Some of the specific needs include:
• Operator training in proper handling and assembly of tube sets
and verification of connection integrity to prove system closure
• Inspector training in the handling, visual and integrity testing of
bags, and execution of sampling techniques
• Operator training in the set-up of unit operation assemblies,
disassembly of components, and handling of solid waste
• Training in the execution of Factory Acceptance Testing (FAT)
activities around evaluation of acceptance criteria
Single-use technology implementation will likely require some new
forms of documentation to support validation efforts. While the audit
process for suppliers and vendors will follow more “standard” practices,
the creation of detailed sequence-of-operation documents as part of
the batch record will be somewhat outside-of-the-box from traditional
SOPs. One example of this comes in the assembly of tube sets for unit
Companies may choose to either have tube sets pre-assembled
by a third party supplier (often preferred for complex tube sets)
or fabricate the tube sets internally as part of the manufacturing
operation. How connection verification is documented, the
identification of components is verified, and how proper set-to-set
interface is verified will be important. This interface verification is
similar to the scenarios experienced in the use of transfer panels and
their unique “jumper” configurations in traditional stainless steel-based facilities of the past decade. Many companies will implement
a fixture or “jig” to ensure that proper sequence of installation is
followed and verification of proper installation easily documented.
Early identification and a clear understanding of the SUS design risk
elements is a key to the likely success of the effort. Two unique and key
areas are in closure analysis and supply chain management.
A closed system should be analyzed in three parts:
• The equipment assembly
Examples: bioreactor, vessels, chromatography systems, etc.
• The streams in and out from the system
Examples: compress air, media and buffers, etc.
• Connections and disconnections to the system
Examples: valves, single-use connectors, etc.
The focus is to demonstrate the risk mitigation for each part to confirm
that the SUS operates in a closed manner that can be validated.
Another key aspect of closure analysis is to have agreement
from the team that the definition of closure is agreed upon by all
members. Closure is not a constant. Three of the often-cited definitions
recognized in the industry are:
• Closed system: A system that is designed and operated such that
the product is isolated and never exposed to the environment.
Additions to, and effluents from, closed systems must be
performed in a completely closed fashion. Transfers into or from
these systems must be validated as closed.
• Functionally closed: Closed systems that are opened between
processing operations but are “rendered closed” by a cleaning,
sanitization, or sterilization process that is appropriate or
consistent with the process requirements, whether sterile, aseptic,
or low bioburden.
• Briefly exposed operations: Open processes containing process
materials and/or product intermediates. These open processes
are rendered closed by means of an appropriate closing process.
Definition and validation of the “pre-closure” incubation phase is
With this SUS information defined, it is now the task of the design
team to execute a Process Closure Analysis.
There are a number of areas around supply chain management that
should be addressed for a SUS-based biomanufacturing project. These
• Compatibility of materials
• Quality and testing standards/criteria