Intense pressure to demonstrate increased productivity and a
robust return on R&D investment is leading the pharmaceutical industry to
focus aggressively on cost control and process improvement. To address these
challenges, drug developers are increasingly leveraging lean manufacturing
initiatives. Based on principles largely developed by Toyota, lean manufacturing seeks to identify
and eliminate waste in order to reduce the cost of bringing a product to
market. Centered on creating more value with less work, lean manufacturing
generally focuses on reducing eight specified wastes to improve overall
customer value (Table 1).

 

In parallel with this focus on lean process improvement, the
industry is actively evaluating and leveraging single-use products and systems
to reduce costs, increase productivity, and speed time to market. The move to
single-use solutions, either alone or in conjunction with stainless steel, is
likely to continue growing in an effort to address these imperatives.

 

When managed properly, implementation of single-use systems
can deliver key benefits as defined in the principles of lean manufacturing:

 

• Improved quality

 

• Reduced waste

 

• Increased productivity

 

• Optimized resource utilization 

 

This article will highlight industry trends that are driving
adoption of single-use systems and describe the implementation of single-use
filtration to deliver lean process improvement efficiencies and drive waste out
from the manufacturing workflow.

 

A Market in Transition

 

The biopharmaceutical industry is undergoing a number of
changes that are having a significant impact on manufacturing (Table 2).

 

Where once a few major drug companies were the industry
leaders and had little competition, contract manufacturing organizations (CMOs)
and generic manufacturers are now playing an increasing role in bringing drugs
to the market. Adding to this new reality is the need to evolve from a focus on
large batches manufactured at a single facility to production of numerous, low
volume, high variability batch runs at multiple facilities around the world.

 

One of the most challenging trends is the shift of drug
development phases (research and development, pilot scale, commercial scale
manufacturing) from single, vertically integrated facilities to separate
locations around the world. While use of multiple sites across multiple
countries can bring great value into the system, the practice puts increased
demands on technology transfer processes.

 

Different manufacturing equipment, materials, and design may
be used in each phase, presenting significant process optimization and
validation challenges due to inconsistencies among bioprocess equipment across
scales. Rapid and seamless technology transfer processes are thus essential to
maintain consistency across all scales.

 

In an effort to address these challenges, many manufacturers
are turning to single-use manufacturing solutions. The benefits of single-use
products in manufacturing are widely known and well-documented. When
implemented properly, single-use systems can accelerate production, improve
flexibility, reduce costs and waste – benefits that are well-aligned with lean
process initiatives.

 

What can prevent a company from fully realizing these
benefits, however, is the manner in which single-use systems are sometimes
employed – on an ad hoc basis without a cohesive plan for applying the
technology across all process scales. Lack of an overarching single-use
strategy can actually increase process inefficiencies (Table 3).

 

When single-use assemblies are sourced from different
vendors, inefficiencies can be amplified as operators must become familiar with
multiple systems, and components are likely to have different expiration dates
and lack compatibility. Further, a smooth and seamless technology transfer
process may be much more challenging when different materials are used at
various manufacturing scales.

 

Consideration of the principles of lean process improvement
during implementation of single-use systems can help ensure that maximum value
is achieved.

 

Delivering Value with Single-use Filtration

 

In order to deliver lean process benefits, single-use
systems must be able to speed production processes, reduce the risk of
deviations, maintain consistency, and have an immediate and favorable impact on
the bottom line through improved efficiency. Assemblies must effectively keep
pace with changing product, scale and site requirements via a modular structure
that is replicable and scalable across geographies.

 

To fully support lean initiatives, the single-use filtration
system should offer fully optimized, customized and integrated assemblies, and
reduce waste.

 

Single-use storage and filtration systems based on Mobius®
Flexible Filtration approach (EMD Millipore) are designed to target the wastes
identified by lean process initiatives: overproduction, defects, excess
inventory, overprocessing, unnecessary transportation and motion, waiting, and
underutilized talent (Table 4).

 

Most critical to the successful implementation of single-use
systems and delivery of the full array of benefits, however, is the applications
support process. This practice brings together users, applications engineers
and lean process improvement experts. Through observation of existing process
and direct interface with operators, performance gaps and opportunities for
improvement are identified.

 

The team then works in a collaborative fashion to develop
the new process designed on Flexible Filtration principles. 

 

Reducing Process Production Time

 

We have found that single-use filration assemblies can
reduce processing time by as much as 50% through decreased preparation and
set-up time. A number of innovative elements are the drivers of this reduction.
A modular manifold design allows a manifold to be built on site, to scale as
needed. The easy filling bag design eliminates the need for operator handling
during bag filling. A universal bag design and scalable sterile filtration
assemblies facilitate technology transfer between early development, late
development and commercial manufacturing. Unique disconnection technology
reduces the time required for sterile disconnection to less than a minute as
compared to five to ten minutes required by a tube sealer.

 

Improving Process Consistency

 

As with any lean process initiative, the ability of
single-use technologies to consistently deliver the full range of expected
benefits depends on a thorough assessment of the current processes,
opportunities for improvement, and a clear definition of objectives. 

 

To this end, EMD Millipore mimics the customer’s pilot
manufacturing setup in our Biomanufacturing Sciences and Training Center
(BSTC, Figure 1). The center enables prototyping of solutions and performance
testing in a laboratory setting before the definitive solution is finalized and
delivered. Consultants review process parameters such as flow rate and pressure
drop requirements, and recommend appropriate filter membrane and size when
designing filtration sub-assemblies.

 

As many as ten to fifteen operators can gather at the
training center to see, touch, and use the prototypes in the training center.
Hands-on testing gives operators a greater degree of confidence than a typical
new processing setup might foster. In addition, operators can provide real-time
feedback, allowing the solution to be better adapted to their actual process.

 

Facilitating Tech Transfer

 

The effectiveness of the technology transfer process is
critical to maintaining product quality and speeding time-to-market. Use of
different systems from different vendors can impede an efficient and accurate
transfer and force processes developed at one scale to be recreated and
re-optimized at other scales.

 

Use of replicable, modular single-use systems help
facilitate cost-effective and timely technology transfer across multiple sites
and different scales.

 

Impacting the Bottom Line

 

Table 4 summarizes the reduction in waste that can be
achieved through proper incorporation of single-use systems. Properly
established single-use systems can deliver as much as a 20% reduction in
materials usage.

 

In addition to significant reductions in processing time and
waste, Flexible Filtration based single-use systems can significantly reduce
the number of part numbers needed to be maintained. One customer has reported
to us a 70% reduction in material master maintenance when the number of single-use
vendors was consolidated; with each new catalog number requiring an investment
of up to $1200 to maintain it annually in an ERP system, this reduction
represents an impressive cost savings.

 

Perspective

 

Drug developers are actively exploring and leveraging
single-use operations to deliver lean process improvements. When incorporated
as part of an overall strategy to reduce waste and process time, improve
process consistency, and facilitate technology transfer, single-use systems
designed with lean process improvement principles can deliver measureable
benefits to the bottom line.

 

Critical success factors include consolidation of single-use
vendors and equipment to minimize variability and create consistency across
processes, and a collaborative approach with applications support engineers and
lean process improvement experts to assess current process and identify
opportunities for improvement.